Major Genetic Syndromes
Familial Adenomatous Polyposis (FAP)
Adenomatous polyposis coli (APC)
Density of colonic polyposis
Genetic testing for FAP
Interventions for FAP
Attenuated Familial Adenomatous Polyposis (AFAP)
MYH-Associated Polyposis (MAP)
Mut Y Homolog
Lynch Syndrome (LS)
Historical criteria for defining LS families
Genetic/molecular testing for LS
Interventions for LS
Chemoprevention in LS
Screening for endometrial cancer in LS families
Surgical management in LS
Advances in Endoscopic Imaging in Hereditary CRC
Small bowel imaging
Familial colorectal cancer type X (FCCX)
Interventions for family history of CRC
Rare Colon Cancer Syndromes
PTEN hamartoma tumor syndromes (including Cowden syndrome)
Peutz-Jeghers syndrome (PJS)
Juvenile polyposis syndrome (JPS)
Hereditary mixed polyposis syndrome (HMPS)
Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPPS)
Interventions for rare colon cancer syndromes
Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient and family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch I and II syndromes, Peutz-Jeghers syndrome [PJS], Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first five, while hamartomas were found to be characteristic in the last three.
With the development of the Human Genome Project and the identification in 1990 of the adenomatous polyposis coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by mutations in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations as having FAP mutation on the 3’ and 5’ ends of the gene. Turcot syndrome families were shown to be genetically part of FAP with medulloblastomas and Lynch syndrome (LS) with glioblastomas. Muir-Torre and LS were shown to have genetic similarities. MYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the mutations were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for mutation carriers (see Table 4).Table 4. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer Syndromes
|Syndrome||Absolute Risk in Mutation Carriers|
|FAPa||90% by age 45 y |
|Attenuated FAP||69% by age 80 y |
|LS||40% to 80% by age 75 yb [3,4]|
|MYH-associated polyposis||35% to 53% |
|PJS||39% by age 70 y |
|JPS||17% to 68% by age 60 y [7,8]|
|FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; LS = Lynch syndrome; PJS = Peutz-Jeghers syndrome.|
|aCancer risk estimates quoted here predate the widespread use of surveillance and prophylactic surgery.|
|bRefer to the Lynch syndrome (LS) section of this summary for a full discussion of risk.|
With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for mutations in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron -exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic mutations from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance that cannot be used for predictive purposes.Familial Adenomatous Polyposis (FAP)
FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,9,10] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births, with the syndrome being more common in Western countries. Autosomal dominant inheritance means that affected persons are genetically heterozygous, such that each offspring of a patient with FAP has a 50% chance of inheriting the disease gene. Males and females are equally likely to be affected.
Classically, FAP is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. Variant features in addition to the colonic polyps may include polyps in the upper gastrointestinal (GI) tract, extraintestinal manifestations such as congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignant changes such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors, particularly medulloblastoma (see Table 5).Table 5. Extracolonic Tumor Risks in Familial Adenomatous Polyposis
|Malignancy||Relative Risk||Absolute Lifetime Risk (%)|
|Adapted from Giardiello et al., Jagelman et al., Sturt et al., Lynch et al., Bülow et al., Burt et al., and Galiatsatos et al.|
|aThe Leeds Castle Polyposis Group.|
FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner syndrome (colorectal polyposis, osteomas, and soft tissue tumors). Gardner syndrome has sometimes been used to designate FAP patients who manifest these extracolonic features. However, Gardner syndrome has been shown molecularly to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.
Most cases of FAP result from mutations of the APC gene on chromosome 5q21. Individuals who inherit a mutant APC gene have a very high likelihood of developing colonic adenomas; the risk has been estimated to be more than 90%.[1,9,10] The age at onset of adenomas in the colon is variable: By age 10 years, only 15% of FAP gene carriers manifest adenomas; by age 20 years, the probability rises to 75%; and by age 30 years, 90% will have presented with FAP.[1,9,10,20,21] Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.[1,9,10] Thus, surveillance and intervention for APC gene mutation carriers and at-risk persons have conventionally consisted of annual sigmoidoscopy beginning around puberty. The objective of this regimen is early detection of colonic polyps in those who have FAP, leading to preventive colectomy.[22,23]
The early appearance of clinical features of FAP and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of children for susceptibility genes. Some proponents feel that the genetic testing of children for FAP presents an example in which possible medical benefit justifies genetic testing of minors, especially for the anticipated 50% of children who will be found not to be mutation carriers and who can thus be spared the necessity of unpleasant and costly annual sigmoidoscopy. The psychological impact of such testing is currently under investigation and is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary.
A number of different APC mutations have been described in a series of FAP patients. The clinical features of FAP appear to be generally associated with the location of the mutation in the APC gene and the type of mutation (i.e., frameshift mutation vs. missense mutation). Two features of particular clinical interest that are apparently associated with APC mutations are (1) the density of colonic polyposis and (2) the development of extracolonic tumors.Adenomatous polyposis coli (APC)
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and AFAP. Both conditions can be diagnosed genetically by testing for germline mutations in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating mutations, primarily in the first half of the gene.[25,26] AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.[27-30]
More than 300 different disease-associated mutations of the APC gene have been reported. The vast majority of these changes are insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC mutation (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other mutations appear to predominate. Mutations that reduce rather than eliminate production of the APC protein may also lead to FAP.
Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[27-29] There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in or before exon 4 and in the latter two-thirds of exon 15, and that retinal lesions are rarely associated with mutations that occur before exon 9.[29,32] Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.Density of colonic polyposis
Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC mutations, particularly those mutations that occur between codons 169 and 1393. At the other end of the spectrum, sparse polyps are features of patients with mutations occurring at the extreme ends of the APC gene or in exon 9. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section of this summary for more information.)Extracolonic tumors
Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening. Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP.[15,35] Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.[35,36]
Most studies have found that 10% of FAP patients develop desmoids, with reported ranges of 8% to 38%. The incidence varies with the means of ascertainment and the location of the mutation in the APC gene.[35,37,38] APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[32,36,39,40] Desmoid tumors with a late onset and a milder intestinal polyposis phenotype (hereditary desmoid disease) have been described in patients with mutations at codon 1924.
A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors. The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. The authors concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale were recently supported by a large, multiregistry, retrospective study from Europe.
The natural history of desmoids is variable. Some authors have proposed a model for desmoid tumor formation whereby abnormal fibroblast function leads to mesenteric plaque-like desmoid precursor lesions, which in some cases occur before surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors. It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly. Desmoids often occur after surgical or physiological trauma, and both endocrine and genetic factors have been implicated. Approximately 80% of intra-abdominal desmoids in FAP occur after surgical trauma.[45,46]
The desmoids in FAP are often intra-abdominal, may present early, and can lead to intestinal obstruction or infarction and/or obstruction of the ureters. In some series, desmoids are the second most common cause of death after CRC in FAP patients.[47,48] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity. The proposed staging system for intra-abdominal desmoids is as follows: stage I for asymptomatic, nongrowing desmoids; stage II for symptomatic, nongrowing desmoids of 10 cm or less in maximum diameter; stage III for symptomatic desmoids of 11 to 20 cm or for asymptomatic, slow-growing desmoids; and stage IV for desmoids larger than 20 cm, or rapidly growing, or with life-threatening complications.
These data suggest that genetic testing could be of value in the medical management of patients with FAP and/or multiple desmoid tumors. Those with APC genotypes, especially those predisposing to desmoid formation (e.g., at the 3’ end of APC codon 1445), appear to be at high risk of developing desmoids after any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.[37,44,50]
The management of desmoids in FAP can be challenging and can complicate prevention efforts. Currently, there is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included antiestrogens, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone.[51-53] There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed. Significant desmoid tumor regression was reported in seven patients who had symptomatic, unresectable, intra-abdominal desmoid tumors and failed hormonal therapy when treated with chemotherapy (doxorubicin and dacarbazine) followed by meloxicam.
Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments, who had expression of estrogen alpha receptors in their desmoid tissues, were included in a prospective study of raloxifene, given in doses of 120 mg daily. Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 ± 1.8 months after treatment. Response occurred in patients with desmoid plaques and with distinct lesions. Study limitations include small sample size, and the clinical evaluation of response was not consistent in all patients. Several questions remain concerning patients with desmoid tumors not expressing estrogen alpha receptors who have received raloxifene and their outcome and which patients may benefit from this potential treatment.
A second study of 13 patients with FAP-associated desmoids, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months. These results suggest that the combination of these agents may be effective in at least slowing the growth of desmoid tumors. However, the natural history of desmoids is variable, with both spontaneous regression and variable growth rates.
A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years. In this study, some patients had regression, some patients had progression, and some patients had stable disease.
These three studies illustrate some of the problems encountered in the study of desmoid disease in FAP patients:
- The definition of desmoid disease has been used inconsistently.
- In some patients, desmoid tumors do not progress or are very slow growing and may not need therapy.
- There is no consistent, systematic way to evaluate the response to therapy.
- There is no single institution that will enroll enough patients to perform a randomized trial.
No randomized clinical trials using these agents have been performed and their use in clinical practice is based on anecdotal experience only.
Because of the high rates of morbidity and recurrence, in general, surgical resection is not recommended in the treatment of intra-abdominal desmoid tumors. However, some have advocated a role for surgery given the ineffectiveness of medical therapy, even when the potential hazards of surgery are considered, and recognizing that not all desmoids are resectable. A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[56,57] Issues of subject selection are critical in evaluating surgical outcome data. Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.Stomach tumors
The most common FAP-related gastric polyps are fundic gland polyps (FGPs). FGPs are often diffuse and not amenable to endoscopic removal. The incidence of FGPs has been estimated to be as high as 60% in patients with FAP, compared with 0.8% to 1.9% in the general population.[16,18,58-62] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[63,64]
The hyperplastic surface epithelium is, by definition, nonneoplastic. Accordingly, FGPs have not been considered precancerous; in Western FAP patients the risk of stomach cancer is minimally increased, if at all. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue.[18,65] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs. In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients. In the author's view, if a polyp with high-grade dysplasia is identified, polypectomy can be considered with repeat endoscopic surveillance in 3 to 6 months. Consideration for treatment with daily proton-pump inhibitors (PPIs) also may be given.
Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming PPIs.[64,67] FGPs in this setting commonly show a “PPI effect” consisting of congestion of secretory granules in parietal cells, leading to irregular bulging of individual cells into the lumen of glands. To the trained eye, the presence of dysplasia and the concomitant absence of a characteristic PPI effect can be considered highly suggestive of the presence of underlying FAP. The number of FGPs tends to be greater in FAP than that seen in patients consuming PPIs, although there is some overlap.
Gastric adenomas also occur in FAP patients. The incidence of gastric adenomas in Western patients has been reported to be between 2% and 12%, whereas in Japan, it has been reported to be between 39% and 50%.[68-71] These adenomas can progress to carcinoma. FAP patients in Korea and Japan are reported to have a threefold to fourfold increased gastric cancer risk compared with their general population, a finding not observed in Western populations.[72-75] The recommended management for gastric adenomas is endoscopic polypectomy. The management of adenomas in the stomach is usually individualized based on the size of the adenoma and the degree of dysplasia.
Level of evidence: None assignedDuodenum/small bowel tumors
Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper GI endoscopy, duodenal adenomas are found in 80% to 100% of FAP patients. The vast majority are located in the first and second portions of the duodenum, especially in the periampullary region.[58,59,77] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[13,74,78,79] In a prospective multicenter surveillance study of duodenal adenomas in 368 northern Europeans with FAP, 65% had adenomas at baseline evaluation (mean age, 38 years), with cumulative prevalence reaching 90% by age 70 years. In contrast to earlier beliefs regarding an indolent clinical course, the adenomas increased in size and degree of dysplasia during the 8 years of average surveillance, though only 4.5% developed cancer while under prospective surveillance. While this study is the largest to date, it is limited by the use of forward-viewing rather than side-viewing endoscopy and the large number of investigators involved in the study. Another modality through which intestinal polyps can be assessed in FAP patients is capsule endoscopy.[80-82] One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.
A retrospective review of FAP patients suggested that the adenoma-carcinoma sequence occurred in a temporal fashion for periampullary adenocarcinomas with a diagnosis of adenoma at a mean age of 39 years, high-grade dysplasia at a mean age of 47 years, and adenocarcinoma at a mean age of 54 years. A decision analysis of 601 FAP patients suggested that the benefit of periodic surveillance starting at age 30 years led to an increased life expectancy of 7 months. Although polyps in the duodenum can be difficult to treat, small series suggest that they can be managed successfully with endoscopy but with potential morbidity—primarily from pancreatitis, bleeding, and duodenal perforation.[85,86]
FAP patients with particularly severe duodenal polyposis, sometimes called dense polyposis, or with histologically advanced duodenal adenomas appear to be at the highest risk of developing duodenal adenocarcinoma.[16,79,87,88] Because the risk of duodenal adenocarcinoma is correlated with the number and size of polyps, and the severity of dysplasia of the polyps, a stratification system based on these features was developed to attempt to identify those individuals with FAP at highest risk of developing duodenal adenocarcinoma. According to this system, known as the Spigelman Classification (see Table 6), 36% of patients with the most advanced stage will develop carcinoma.Table 6. Spigelman Classification
|Points||Polyp Number||Polyp Size (mm)||Histology||Dysplasia|
|Stage I, 1–4 points; Stage II, 5–6 points; Stage III, 7–8 points; Stage IV, 9–12 points |
A baseline upper endoscopy, including side-viewing duodenoscopy, should be performed between ages 25 and 30 years in FAP patients. The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often, based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0-II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial (see Table 7).
The main advantages of the Spigelman Classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies.[71,89] However, there are several limitations on attempted application of the Spigelman Classification:
- Most pathologists do not currently employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
- Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of “tubular,” “tubulovillous,” and “villous.”
- Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.[90,91]
|Spigelman Stage||NCCN (2014) ||Groves et al. (2002) |
|0 (no polyps)||Endoscopy every 4 y||Endoscopy every 5 y|
|I||Endoscopy every 2–3 y||Endoscopy every 5 y|
|II||Endoscopy every 1–3 y||Endoscopy every 3 y|
|CP + ET|
|III||Endoscopy every 6–12 mo||Endoscopy every 1–2 y|
|CP + ET (+/- GA)|
|IV||Surgical referral||Surgical resection|
|Complete mucosectomy or duodenectomy or Whipple procedure if duodenal papilla is involved|
|Expert endoscopic surveillance every 3–6 mo||Endoscopy every 1–2 y|
|CP + ET (+/- GA)|
|CP = chemoprevention; ET = endoscopic therapy; GA = general anesthetic; NCCN = National Comprehensive Cancer Network.|
|Refer to the Interventions for FAP section in the Major Genetic Syndromes section of this summary for more information about chemoprevention.|
|See below for additional information about the use of surgical resection in Spigelman stage IV disease.|
Many factors, including severity of polyposis, comorbidities of the patient, patient preferences, and availability of adequately trained physicians, determine whether surgical or endoscopic therapy is selected for polyp management. Endoscopic resection or ablation of large or histologically advanced adenomas appears to be safe and effective in reducing the short-term risk of developing duodenal adenocarcinoma;[85,86,93] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum. The most definitive procedure for reducing the risk of adenocarcinoma is surgical resection of the ampulla and duodenum, though these procedures also have higher morbidity and mortality associated with them than do endoscopic treatments. Duodenotomy and local resection of duodenal polyps or mucosectomy have been reported, but invariably, the polyps recur after these procedures. In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate is dramatically lower than any local endoscopic or surgical approach from the same study. Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[91,94-96] If such surgical options are considered, preservation of the pylorus is of particular benefit in this group of patients because most will have undergone a subtotal colectomy with ileorectal anastomosis or total colectomy with ileal pouch–anal anastomosis (IPAA). As noted in a Northern European study, and others,[97,98] the vast majority of patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.
The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) after submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly “lift” with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention.[86,90,91,95,99-102] The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.
Reluctance to consider surgical resection has to do with short-term morbidity and mortality and long-term complications related to surgery. Although these concerns are likely overstated,[90,91,96,99,103-109] fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. This is, however, associated with a high risk of local recurrence similar to that of endoscopic treatment.Other tumors
The spectrum of tumors arising in FAP is summarized in Table 5.
Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP. However, a recent study  of papillary thyroid cancers in six females with FAP failed to demonstrate loss of heterozygosity (LOH) or mutations of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four out of five of these patients had detectable somatic RET/PTC chimeric genes. This mutation is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC mutations. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC mutations in causing papillary thyroid cancers in FAP patients. Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasounds to this screening routine.[92,112,113]
Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient. In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors. Of these, two had symptoms attributable to cortisol hypersecretion. Three of these patients underwent subsequent surgery and were found to have adrenocortical carcinoma, bilateral nodular hyperplasia, or adrenocortical adenoma. The prevalence of an unexpected adrenal neoplasia in this cohort was 7.4%, which compares with a prevalence of 0.6% to 3.4% (P < .001) in non-FAP patients. No molecular genetic analyses were provided for the tumors resected in this series.
Hepatoblastoma is a rare, rapidly progressive, and usually fatal childhood malignancy that, if confined to the liver, can be cured by radical surgical resection. Multiple cases of hepatoblastoma have been described in children with an APC mutation.[116-125] Some series have also demonstrated LOH of APC in these tumors.[117,119,126] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma. Although lacking level 1 evidence, a consensus panel has recommended abdominal examination, abdominal ultrasound, and measurement of serum alpha fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP.[92,128]
The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with mutations in APC, while colon cancer and glioblastoma are associated with mutations in mismatch repair (MMR) genes.
There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a mutation of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.Genetic testing for FAP
APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not mutation carriers. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage  and direct detection  of APC mutations. These tests require a small sample (<10 cc) of blood in which the lymphocyte DNA is tested. If one were to use linkage analysis to identify gene carriers, ancillary family members, including more than one affected individual, would need to be studied. With direct detection, fewer family members’ blood samples are required than for linkage analysis, but the specific mutation must be identified in at least one affected person by DNA mutation analysis or sequencing. The detection rate is approximately 80% using sequencing alone.
Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[132,133] For this reason, deletion testing has been added as an optional adjunct to sequencing of APC. Furthermore, mutation detection assays that use MLPA are being developed and appear to be accurate for detecting intragenic deletions. MYH gene testing may be considered in APC mutation–negative affected individuals. (Refer to the Adenomatous polyposis coli (APC) section of this summary for more information.)
Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis should include AFAP and MYH-associated colorectal neoplasia (also reported as MYH-associated polyposis or MAP). AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section in the Major Genetic Syndromes section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.
Presymptomatic genetic testing removes the necessity of annual screening of at-risk individuals who do not have the familial gene mutation. For at-risk individuals who have been found to be definitively mutation-negative by genetic testing, there is no clear consensus on the need for or frequency of colon screening, though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years).[20,21] Colon adenomas will develop in nearly 100% of persons who are APC gene mutation positive; risk-reducing surgery comprises the standard of care to prevent colon cancer after polyps have appeared and are too numerous or histologically advanced to monitor safely using endoscopic resection.Interventions for FAP
Individuals at risk of FAP, because of a known APC mutation in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is eventual colectomy. In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.
The recommended age at which surveillance for polyposis should begin involves a trade-off. On the one hand, someone who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, CRC can develop in a teenager who carries an APC mutation. On the other hand, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance is usually begun in the early teenage years (age 10–15 years). Surveillance has consisted of either flexible sigmoidoscopy or colonoscopy every year.[92,138,139] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Historically, sigmoidoscopy may have been a reasonable approach at the time in identifying early adenomas in a majority of the patients. However, colonoscopy must be considered the tool of choice in light of (a) improved instrumentation for full colonoscopy, (b) safer and deeper sedation (Propofol), (c) recognition of AFAP, in which the disease is typically most manifest in the right colon, and (d) the growing tendency to defer surgery for a number of years. Individuals who have tested negative for an otherwise known family mutation do not need FAP-oriented surveillance at all. They are recommended to undergo average-risk population screening. In the case of families in which no family mutation has been identified in an affected person, then clinical surveillance is warranted. Colon surveillance should not be stopped in persons who are known to carry an APC mutation but who do not yet manifest polyps, since adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section of this summary for more information.) (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)
In some circumstances, full colonoscopy may be preferred over the more limited sigmoidoscopy. Among pediatric gastroenterologists, tolerability of endoscopic procedures in general has been regarded as improved with the use of deeper intravenous sedation.
Table 8 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP)
|Organization||APC Gene Test Recommended||Age Screening Initiated||Frequency||Method||Comment|
|American Society of Colon and Rectal Surgeons (2001, 2003) [140-142]||Yes||NA||NA||NA|
|American Cancer Society (2002) ||NA||Puberty||NA||Endoscopy||Referral to a center specializing in FAP screening suggested.|
|GI Societies (2003)a ||Yes||10–12 y||Annual||FS|
|NCCN (2014) ||Yes||10–15 y||Annual||FS or C||Consider MYH mutation testing if APC testing is negative and family history is compatible with recessive inheritance; in families in which no mutation is found, offspring of those affected are screened as if they were carriers.|
|C = colonoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; NA = not addressed; NCCN = National Comprehensive Cancer Network.|
|aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.|
Once an FAP family member is found to manifest polyposis, colectomy is the only effective management. Patient and doctor should enter into an individualized discussion to decide when surgery should be performed. It is useful to incorporate into the discussion the risk of developing desmoid tumors after surgery. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology. Once numerous polyps have developed, surveillance colonoscopy is no longer useful in timing the colectomy because polyps are so numerous that it is not possible to biopsy or remove all of them. At this time, it is appropriate for patients to consult with a surgeon who is experienced with available options, including total colectomy and postcolectomy reconstruction techniques. Rectum-sparing surgery, with sigmoidoscopic surveillance of the remaining rectum, is a reasonable alternative to total colectomy in those compliant individuals who understand the consequences and make an informed decision to accept the residual risk of rectal cancer occurring despite periodic surveillance.
Surgical options include restorative proctocolectomy with IPAA, subtotal colectomy with ileorectal anastomosis (IRA), or total proctocolectomy with ileostomy (TPC). TPC is reserved for patients with low rectal cancer in which the sphincter cannot be spared or for patients on whom an IPAA cannot be performed because of technical problems. There is no risk of developing rectal cancer after TPC because the whole mucosa at risk is removed. Whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. This is necessitated by case series of rectal cancers arising in the rectum of FAP patients who had subtotal colectomies with an IRA in which there was an approximately 25% cumulative risk of rectal adenocarcinoma 20 years after IRA and by case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[147-150] The cumulative risk of rectal cancer after IRA may be lower than that reported in the literature, in part because of better selection of patients for this procedure, such as those with minimal polyp burden in the rectum. Other factors that have been reported to increase the rectal cancer risk after IRA include the presence of colon cancer at the time of IRA, the length of the rectal stump, and the duration of follow-up after IRA.[151-157] An abdominal colectomy with IRA as the primary surgery for FAP does not preclude later conversion to an IPAA for uncontrolled rectal polyps and/or rectal cancer. In the Danish Polyposis Registry, the morbidity and functional results of a secondary IPAA (after a previous IRA) in 24 patients were reported to be similar to those of 59 patients who underwent primary IPAA.
In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery. In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum. Mutations reported to increase the rectal cancer risk and eventual completion proctectomy after IRA include mutations in exon 15 codon 1250, exon 15 codons 1309 and 1328, and exon 15 mutations between codons 1250 and 1464.[156,147,157,161] In patients who have undergone IPAA, it is important to continue annual surveillance of the ileal pouch because the cumulative risk of developing adenomas in the pouch has been reported to be up to 75% at 15 years.[162,163] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients. A meta-analysis of quality of life after restorative proctocolectomy and IPAA has suggested that FAP patients do marginally better than inflammatory bowel disease patients in terms of fistula formation, pouchitis, stool frequency, and seepage.
Celecoxib, a specific cyclooxygenase II (COX-2) inhibitor, and nonspecific COX-2 inhibitors, such as sulindac, have been associated with a decrease in polyp size and number in FAP patients, suggesting a role for chemopreventive agents in the treatment of this disorder.[166,167] Although celecoxib had been approved by the U.S. Food and Drug Administration (FDA), its license was voluntarily withdrawn by the manufacturer. Currently, there are no FDA-approved drugs for chemoprevention in FAP. Nevertheless, agents such as celecoxib and sulindac are in sufficiently widespread use that chemopreventive clinical trials typically utilize one of these agents as the control arm.
A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 years) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period. This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day, which approximates the approved dose of 400 mg twice daily in adults, the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.
Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP post subtotal colectomy. Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.
It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind, placebo-controlled trial in 41 APC mutation carrier children and young adults who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.
Consistent with the effects of COX-2 inhibitors on colonic polyps, in a randomized, prospective, double-blind, placebo-controlled trial, celecoxib (400 mg, administered orally twice daily) reduced, but did not eliminate, the number of duodenal polyps in 32 patients with FAP after a 6-month course of treatment. Of importance, a statistically significant effect was seen only in individuals who had more than 5% of the duodenum involved with polyps at baseline and with an oral dose of 400 mg, given twice daily. A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps. The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply to their use for the treatment of duodenal polyps (e.g., only partial elimination of the polyps, complications secondary to the COX-2 inhibitors, and loss of effect after the medication is discontinued).
Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[172-175] it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.
One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac (an NSAID) treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, CRC incidence.
Patients who carry APC germline mutations are at increased risk of other types of malignancies, including thyroid cancer, small bowel cancer, hepatoblastoma, and brain tumors. The risk of these tumors, however, is much lower than that for colon cancer, and the only surveillance recommendation by experts in the field is upper endoscopy of the gastric and duodenal mucosa.[9,22] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma. (Refer to the Duodenum/small bowel tumors section and the Other tumors section in the Major Genetic Syndromes section of this summary for more information about screening for extracolonic malignancies in patients with FAP.)Attenuated Familial Adenomatous Polyposis (AFAP)
AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds. Adenomas in AFAP are believed to form in the mid-twenties to late twenties. Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[27,28,178] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (FGPs, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.
- Mutations associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper GI polyps.
- Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
- 3’ region mutations in which patients have very few adenomas (<50).
APC gene testing is an important component of the evaluation of patients suspected of having AFAP. It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided. The role for and timing of risk-reducing colectomy in AFAP is controversial. If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[183,184] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), LS, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or LS.
Table 9 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.Table 9. Clinical Practice Guidelines for Colon Surveillance of Attenuated Familial Adenomatous Polyposis (AFAP)
|Organization||Condition||Screening Method||Screening Frequency||Age Screening Initiated||Comment|
|Europe Mallorca Group (2008) ||AFAP||Colonoscopy||Every 2 y; every 1 y if adenomas are detected||18–20 y|
|NCCN (2014) ||Personal history of AFAP with small adenoma burdena||Colonoscopy||Every 1–2 y||If patient had colectomy with IRA due to significant polyposis not manageable with polypectomy, endoscopic evaluation every 6–12 mo depending on polyp burden.|
|Colectomy and IRA may be considered in patients aged ≥21 y|
|NCCN (2014) ||Personal history of AFAP with significant polyposis||Not applicable||Not applicable||Not applicable||Colectomy with IRA preferred. Consider proctocolectomy with IPAA if dense rectal polyposis.|
|NCCN (2014) ||Unaffected, at-risk family member; family mutation unknown; APC mutation status unknown or positive||Colonoscopy||Every 2–3 y||Late teens|
|IPPA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network.|
|aFewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.|
MYH-Associated Polyposis (MAP)
MAP is an autosomal recessive inherited polyposis syndrome. The MYH gene was first identified in 2002 in three siblings with multiple colonic adenomas and CRC but no APC mutation. MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and LS. MAP patients tend to develop fewer adenomas at a later age than patients with APC mutations [135,187] and also carry a high risk of CRC (35%–63%).[5,188] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MYH mutations of 4% (95% confidence interval [CI], 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas. This broad clinical presentation results from the MYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[5,135,190,191]
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients. The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC. Clinical management guidelines for biallelic MAP range between once a year to every 3 years for colonoscopic surveillance beginning at age 18 to 30 years,[92,185,188] with upper endoscopic surveillance beginning at age 25 to 30 years. (Refer to Table 10 for more information about available clinical practice guidelines for colon surveillance in biallelic MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria. Total colectomy with ileorectal anastomosis or subtotal colectomy may be appropriate for patients with MYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.[188,193]
Table 10 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.Table 10. Clinical Practice Guidelines for Colon Surveillance of Biallelic MYH-Associated Polyposis (MAP)
|Organization||Condition||Screening Method||Screening Frequency||Age Screening Initiated||Comment|
|Europe Mallorca Group (2008) ||Biallelic MYH mutation carrier||Colonoscopy||Every 2 y||18–20 y|
|Nieuwenhuis et al. (2012) ||Biallelic MYH mutation carrier||Colonoscopy||Every 1–2 y|
|NCCN (2014) ||Personal history of MAP, small adenoma burdena||Colonoscopy||Every 1–2 y||If patient had colectomy with IRA due to significant polyposis not manageable with polypectomy, endoscopic evaluation every 6–12 mo depending on polyp burden.|
|Colectomy and IRA may be considered in patients aged ≥21 y|
|NCCN (2014) ||Personal history of MAP with significant polyposis||Not applicable||Not applicable||Not applicable||Colectomy with IRA preferred. Consider proctocolectomy with IPAA if dense rectal polyposis. If patient had colectomy with IRA, then endoscopic evaluation of rectum every 6–12 mo depending on polyp burden.|
|NCCN (2014) ||Unaffected, at-risk family member; family mutation unknown; MYH mutation status unknown or positive (biallelic)||Colonoscopy||Every 2–3 y||25–30 y||If positive for a single MYH mutation, follow average-risk colorectal screening.|
|IPAA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network.|
|aFewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.|
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas.[194,195] Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[135,195-197] Female MAP patients have an increased risk of breast cancer. These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.[199,200]
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and its role in pathogenesis of polyposis coli and colorectal carcinoma remains in dispute. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH.[5,135,137] A 2011 meta-analysis found that monoallelic MYH mutation carriers are at modest increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of monoallelic mutation carriers, they account for only a trivial proportion of all CRC cases. Although some studies have suggested screening these individuals on the basis of this modest increase in risk, others have suggested following screening recommendations for the general population.
MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).Mut Y Homolog
The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1. The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations. Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.Oligopolyposis
Oligopolyposis is a popular term used to describe the clinical presentation of a polyp count or burden that is greater than anticipated in the course of screening in average-risk patients but that falls short of the requirement for a diagnosis of FAP. Thus, oligo-, Greek for few, can mean different things to different observers. While conceding a lack of consensus on the matter, the National Comprehensive Cancer Network (NCCN) committee on CRC screening suggests an AFAP diagnosis is worth considering when 10 to 100 adenomas are present. It will be used here to describe the circumstance in which the polyp count (generally adenoma) is large enough, with or without any attendant family history, to raise in the mind of the endoscopist the possibility of an inherited susceptibility.
In the setting of known or suspected LS, the detection of one to ten adenomas is still in keeping with the diagnosis. A similar adenoma count in a young patient undergoing colonoscopy for symptoms or in a screening patient over age 50 years could raise the question of LS. In the appropriate clinical setting—early onset and positive family history—the detection of any number of adenomas may support the testing and diagnosis of a patient for underlying LS mutations, consistent with guidelines such as those offered by the NCCN. Some controversy exists over the utility of testing adenoma tissue for microsatellite instability (MSI), as the yield is lower than in invasive cancer. In general, and subject to the above caveats, LS is not routinely considered in a discussion of oligopolyposis.
One study considered a series of polyps (37 adenomas) from 21 patients with known MMR mutations, performing MSI and immunohistochemistry (IHC) for MMR protein expression. Overall, MSI-high (MSI-H) was seen in 41% and in 100% of adenomas larger than 1 cm. Adenomas measuring smaller than 1 cm yielded MSI about 30% of the time. Correlation between MSI and loss of staining on IHC was fairly high, although the discordance rate (17%) was higher than in other series that evaluated invasive cancers from known MMR mutation carriers. A higher MSI likelihood was observed in subjects older than 50 years. IHC staining in relation to mutation showed 8 of 12 MLH1 adenomas to have lost protein expression, with 10 of 20 adenomas from MSH2 patients to have loss of expression. In contrast, none (0 of 6) of the adenomas from MSH6 mutation carriers had loss of associated protein expression. The authors concluded that while normal MSI/IHC was simply not informative, abnormal MSI/IHC was as likely in larger (>8 mm) polyps as in cancers and thus a reasonable test to consider.
AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC mutation are clearly variant cases of FAP, as the term AFAP implies. However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC mutation. The lower the polyp count the lower the probability of APC mutation. Some of these cases are now known to carry biallelic MYH mutations, although even here, the lower the adenoma count the lower the mutation likelihood.
Another study evaluated 152 patients with 3 to 100 adenomas and another 107 APC mutation–negative patients with a “classic” FAP polyp burden for evidence of MYH mutations. Six patients with multiple adenomas and eight with a classic FAP burden had biallelic MYH mutations. The authors concluded that a cut-point of about 15 adenomas was a threshold above which MYH testing was reasonable, and many insurance companies in the United States have adopted a policy based on this cumulative adenoma count. Similar mutation rates for MYH biallelic mutations were found by others using 20 adenomas as the threshold for considering testing.
Mutations in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis and endometrial cancer.[209,210] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.
The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternatives mutation testing is uninformative and surveillance akin to that afforded patients with LS or MAP.[209,210] POLE and POLD1 mutation testing is being incorporated into the new multigene CRC susceptibility panels offered commercially.
A majority of patients with oligopolyposis involving adenomas are currently not found to have an underlying predisposition when evaluated for mutations in known predisposition genes. Such cases are generally managed as if they are at an increased risk of recurrent adenomas even when the colon can be “cleared” of polyps endoscopically.
Oligopolyposis caused by juvenile polyposis syndrome (JPS) or PJS can readily be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. Serrated polyposis can present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (≥5 serrated polyps proximal to sigmoid with 2 ≥1 cm, or any number of polyps proximal to sigmoid if there is a relative with serrated polyposis, or >20 serrated polyps anywhere in the colon) have never been validated. Furthermore, no genetic basis has been established, even in the uncommon familial cases. But cases of oligopolyposis of the serrated variety can initially be challenging to distinguish from oligoadenomatosis, particularly when there is an admixture of adenomas. Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MYH biallelic mutations have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in LS. Generally though, the genetic workup of serrated polyposis is unrewarding.[211-215]Lynch Syndrome (LS)
Between 1900 and 1990, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset; high risk of second primary tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as Lynch 1 (families with CRC only), Lynch 2 (families with CRC and extracolonic tumors), cancer family syndrome, and later, hereditary nonpolyposis colorectal cancer (HNPCC), were commonly employed.
By 1990, the need for enhanced surveillance (colonoscopy at an early age and repeated frequently) was recognized. However, the need to limit this aggressive regimen to families most likely to have an inherited susceptibility or “true” HNPCC led to development of the so-called Amsterdam criteria: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.
At about this same time, a chromosomal abnormality on 5q led to detecting genetic linkage between FAP and this genomic region, from which the APC gene was eventually cloned. This led to searches for similar linkage in HNPCC. The APC gene was one of several genes (along with DCC and MCC) evaluated and to which no HNPCC linkage was found. An extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large HNPCC families in 1993. Once MSH2, the first HNPCC gene, was sequenced, it was evident (from the somatic mutation patterns in the tumors) that the mismatch repair (MMR) family of genes was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2. These MMR genes were formerly referred to as hMSH2, hMLH1, hMSH6, and hPMS2, with the “h” designating them as human homologs; for simplicity, the “h” was dropped.
Concurrent with the linkage studies, somatic genetic studies of HNPCC tumors showed evidence of characteristic mutations in microsatellite regions of numerous genes, which appeared to be a molecular marker of MMR deficiency. This was characterized with synonyms such as ubiquitous somatic mutations, replication errors, and eventually, the currently employed term microsatellite instability (MSI). In HNPCC-related tumors showing MSI, there is typically loss of immunohistochemical expression for one or more of the proteins associated with the MMR genes. Since IHC is relatively easy to perform, it can serve to complement or even supplant MSI screening of suspected HNPCC cases. Although MSI characterizes nearly all HNPCC tumors, it can also occur sporadically in about 12% of CRCs. These cases clearly do not have the inherited disorder HNPCC, since further studies have shown that the MSI is caused by somatic inactivation of the MLH1 protein by hypermethylation of the MLH1 promoter. In most instances, the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.
Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.
Against this background of potential clinical selection criteria for mutation testing, population studies have emerged that can estimate HNPCC frequency (1%–3%) and determine the performance characteristics of these same selection tools when implemented in otherwise unselected cases.
The combination of genetic counseling/testing strategies with clinical screening/treatment measures has led to the development of consensus clinical practice guidelines. These guidelines can be used by providers and patients alike to better understand the available options and key decision-points that exist. (Refer to Table 11 for more information about practice guidelines for diagnosis and colon surveillance in LS.)
Terminology related to familial CRC has certainly evolved. Most in the field use the term Lynch syndrome (LS) as a preferred synonym over HNPCC, since HNPCC is both excessively wordy and misleading—many patients have polyps and many have tumors other than CRC. In addition, entities such as Muir-Torre syndrome are now recognized as phenotypic variants of LS. Even Turcot syndrome, which was initially thought to only be an FAP variant, is now known to be an LS variant when it presents with glioblastomas and an FAP variant when it presents with medulloblastomas. It has been suggested that the term LS be applied to cases in which the genetic basis can be confidently linked to a germline mutation in a DNA MMR gene (either a germline mutation is present or can be confidently inferred based on the clinical presentation combined with MSI/IHC).
The term "familial colorectal cancer type X" or "FCCX" was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities. Some refer to FCCX as “Lynch-like syndrome.” Complicating the terminology further, the term “Lynch-like” has also been used in cases with MSI-H tumors and presumed underlying MMR germline mutation, but in which no such mutation is detected.
In LS,[218-220] unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 1% to 3% of all CRCs. LS is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years [221-223] and 71 years in sporadic CRC. In mutation-positive families when probands were excluded and both affected and nonaffected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years, suggesting ascertainment bias in early reports.
The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females. However, in a meta-analysis of three population-based studies and one clinic-based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females.[226,227] In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females. PMS2 lifetime CRC risk to age 70 years has been reported to be 20% in males and 15% in females. A large registry-based study from France estimated CRC risk at age 70 years to be 41% for MLH1 mutation carriers, 48% for MSH2 mutation carriers, and 12% for MSH6 mutation carriers.
These data have been largely retrospective and potentially include some biases for that reason. Some prospective data exist, however. The Colon Cancer Family Registry program followed 446 carriers prospectively and found a 10-year risk of CRC of 8%.
Patients with LS can have synchronous and metachronous colorectal neoplasms and other primary extracolonic malignancies. LS mutation carriers have an increased risk of developing colon adenomas (hazard ratio [HR], 3.4), and the onset of adenomas appears to occur at a younger age than in nonmutation carriers from the same families. Unlike patients with sporadic cancers, whose cancer develops most often in the left side of the colon, approximately two-thirds of LS cancers develop in the right side of the colon, defined as proximal to the splenic flexure.
The most common extracolonic malignancy in LS is endometrial adenocarcinoma, which affects at least one female member in about 50% of LS pedigrees. Fifty percent of women with a MMR gene mutation will present with endometrial cancer as their first malignancy.
The lifetime risk of endometrial cancer has been estimated to be from 44% in MLH1 mutation carriers to 71% in MSH2 mutation carriers.[225-228,234] Families with an MSH6 mutation have been reported to have an endometrial cancer predominance. Lifetime risk of endometrial cancer in MSH6 mutation carriers in 113 families was estimated to be 26% at age 70 years and 44% at age 80 years. In PMS2 mutation carriers, the endometrial cancer risk at age 70 years has been reported to be 15%. The same prospective data collection in the Colon Cancer Family Registry program yielded 5-year endometrial cancer risks of about 3% and 10-year endometrial cancer risks of about 10% in women from this cohort. Women with loss of MSH2 protein expression caused by an EPCAM mutation are also at risk of endometrial cancer. One study found a 12% (95% CI, 0%–27%) cumulative risk of endometrial cancer in EPCAM deletion carriers. A study of 127 women with LS who had endometrial cancer as their index cancer were found to be at significantly increased risk of other cancers. The following elevated risks were reported: CRC, 48% (95% CI, 27.2%–58.3%); kidney, renal pelvis, and ureter cancer, 28% (95% CI, 11.9%–48.6%); urinary bladder cancer, 24.3% (95% CI, 8.56%–42.9%; and breast cancer, 2.51% (95% CI, 1.17%–4.14%).
LS-associated endometrial cancer is not limited to the endometrioid subtype. It most commonly arises from the lower uterine segment. Endometrial adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors are part of the spectrum of uterine tumors in LS. Three cases of endometrial cancer arising from endometriosis in women with LS have been reported. (Refer to the Screening for endometrial cancer in LS families section of this summary for information about screening methods.)
Several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis and cancers of the stomach, small intestine, liver and biliary tract, brain, breast, ovary, prostate, and adrenal cortex.[239-245] The largest prospective study to date is of 446 unaffected mutation carriers from the Colon Cancer Family Registry. Participants who were followed for up to 10 years demonstrated an increased standardized incidence ratio (SIR) for colorectal, endometrial, ovarian, gastric, renal, bladder, pancreatic, and breast cancers. With the exception of colorectal, endometrial, and breast cancers, the number of observed cases was very small for most cancers (i.e., two to three cases), resulting in very wide 95% CIs.
The issue of breast cancer risk in LS has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with LS;[246-249] one of these studies evaluated breast cancer risk in individuals with LS and found that it is not elevated. However, the largest prospective study to date of 446 unaffected mutation carriers from the Colon Cancer Family Registry  who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001). The same group subsequently analyzed data on 764 MMR gene mutation carriers with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59). However, further studies are needed to define absolute risks and age distribution before surveillance guidelines for breast cancer can be developed for MMR mutation carriers.
Prostate cancer was found to be associated with LS in a study of 198 families from two U.S. LS registries in which prostate cancer had not originally been part of the family selection criteria. Prostate cancer risk in relatives of MMR gene mutation carriers was 6.3% at age 60 years and 30% at age 80 years, versus a population risk of 2.6% at age 60 years and 18% at age 80 years, with an overall hazard ratio of 1.99 (95% CI, 1.31–3.03). Notwithstanding prevalent controversy surrounding routine prostate-specific antigen (PSA) screening, the authors suggested that screening by means of PSA and digital rectal exam (DRE) beginning at age 40 years in male MMR gene carriers would be “reasonable to consider.”
Another study assessed a series of 114 adrenocortical carcinomas (ACCs). Of 94 patients who had a detailed family history assessment and in whom Li-Fraumeni syndrome testing was nondiagnostic, 3 patients had family histories that were suggestive of LS. The prevalence of MMR gene mutations in 94 families was 3.2%, similar to proportion of LS among unselected colorectal and endometrial cancer patients. In a retrospective review of 135 MMR gene mutation–positive LS families from the same program, two probands were found to have had a history of ACC. Of the four ACCs in which MSI testing could be performed, all were microsatellite stable (MSS). These data suggest that if LS is otherwise suspected in an ACC index case, an initial evaluation of the ACC using MSI or IHC testing may be misleading.
Muir-Torre syndrome is considered a variant of LS and includes a phenotype of multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas). The skin lesions and CRC define the phenotype,[251,252] and clinical variability is common. Both mutations in the MSH2 and MLH1 genes have been found in Muir-Torre families.[253-255] A study of 1,914 MSH2 and MLH1 unrelated probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype.Historical criteria for defining LS families
The research criteria for defining LS families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990 and are known as the Amsterdam criteria. These criteria were limited to CRC. In 1999, the Amsterdam criteria were revised to include some extracolonic cancers. These criteria provide a general approach to identifying LS families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline MMR gene mutations, have been reported.
Amsterdam criteria I (1990):
- One member diagnosed with CRC before age 50 years.
- Two affected generations.
- Three affected relatives, one of them a first-degree relative of the other two.
- FAP should be excluded.
- Tumors should be verified by pathological examination.
Amsterdam criteria II (1999):
- Same as Amsterdam criteria I, but tumors of the endometrium, small bowel, ureter, or renal pelvis can be used to substitute an otherwise qualifying CRC.
Although these criteria are the most stringent used to identify potential candidates for microsatellite and germline testing, it must be cautioned that by definition, FCCX includes families meeting Amsterdam criteria but in whom there is no evidence of MSI. (Refer to the Familial colorectal cancer type X (FCCX) section in the Major Genetic Syndromes section of this summary for more information.)
Recognizing both the relative insensitivity of the Amsterdam criteria and the increasing importance of tumor-based testing for detecting LS, the Bethesda guidelines were developed. The Bethesda guidelines and a subsequent revision were formulated to improve sensitivity by targeting patients whose tumors would be most likely to show MSI.[259,260] (Refer to the Genetic/molecular Testing for LS section in the Major Genetic Syndromes section of this summary for more information about testing for MSI and IHC.)
Bethesda guidelines (1997):
- Cancer in families that meet the Amsterdam criteria.
- The presence of two LS-related cancers, including synchronous and metachronous CRCs or associated extracolonic cancers. [Note: Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell carcinoma of the renal pelvis or ureter.]
- The presence of CRC and a first-degree relative with CRC and/or LS-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed before age 45 years, and the adenoma diagnosed before age 40 years.
- CRC or endometrial cancer diagnosed before age 45 years.
- Right-sided CRC with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed before age 45 years. [Note: Solid/cribriform defined as poorly differentiated or undifferentiated carcinoma composed of irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.]
- Signet-ring-cell-type CRC diagnosed before age 45 years. [Note: Composed of more than 50% signet ring cells.]
- Adenomas diagnosed before age 40 years.
Revised Bethesda Guidelines (2004)*:
- CRC diagnosed in an individual younger than 50 years.
- Presence of synchronous, metachronous colorectal, or other LS-associated tumors.**
- CRC with MSI-H pathologic associated features diagnosed in an individual younger than 60 years. [Note: Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]
- CRC or LS-associated tumor** diagnosed in at least one first-degree relative younger than 50 years.
- CRC or LS-associated tumor** diagnosed at any age in two first-degree or second-degree relatives.
*One criterion must be met to consider the tumor for MSI testing.
**LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[260,261] Data from the Cancer Family Registry suggest that breast and prostate cancers may also be considered in the spectrum of LS-associated tumors.
Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are MSS. A number of these families have been found to have mutations in MSH6.[262-266] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.
Currently, there is a move toward universal testing of colorectal and endometrial tumors. (Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section for more information.)Genetic/molecular testing for LS
Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family.[267,268] Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated.[269-272] Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.
In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed before age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals. Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.MSI/IHC in adenomas
Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance when an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR mutations found 8 of 12 adenomas to have both MSI and IHC protein loss. However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.MSI
Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences.[275,276] The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations. In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.
Certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. These histologic features have been combined into computational scores that have high predictive value in identifying MSI CRCs.[278,279]
Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference. If more than 30% of a tumor's markers are unstable, it is scored as MSI-H; if at least one, but fewer than 30% of markers are unstable, the tumor is designated MSI-low (MSI-L). If no loci are unstable, the tumor is designated MSS. Most tumors arising in the setting of LS will be MSI-H. The clinical relevance of MSI-L tumors remains controversial. The probability of finding a germline mutation in a MMR gene in this setting is very small. One distinction is that people with germline mutations in MSH6 do not necessarily manifest the MSI-H phenotype. One study presented evidence that MSH6 mutations were associated with cancers having an MSI-L phenotype. However, a second study found that 18 of 21 (86%) of CRCs in MSH6 carriers showed MSI-H. In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.
(Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for information about the utilization of MSI status in the diagnostic work-up of a patient with suspected LS.)
(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about the practice and feasibility of universal testing and issues related to informed consent for MSI and IHC testing.)The complexity of aberrant methylation of MMR genes
Aberrant MLH1 methylation in sporadic CRC
The presence of an MSI-H tumor associated with loss of MSH2, MSH6, or PMS2 protein expression strongly supports a diagnosis of LS. However, MSI-H tumors with absent MLH1 protein expression present a more complex scenario. MSI occurs in approximately 10% to 15% of sporadic CRC (generally, patients aged >50 years and with little or no family history). In sporadic CRC, absent MLH1 protein expression is a consequence of aberrant MLH1 methylation, a somatic event confined to the tumor that in the vast majority of cases is not heritable. Since loss of MLH1 protein expression occurs in both LS and sporadic tumors, its specificity for predicting germline MMR gene mutations is lower than for the other MMR proteins.
Because of this uncertainty, additional molecular testing is often necessary to clarify the etiology of MLH1 absence in these cases. Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals with germline mutations in one of the MMR genes are BRAF mutations and MLH1 promoter methylation.
Aberrant methylation of MLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers. Other mechanisms such as somatic MLH1 mutations may be responsible for the minority of cases where aberrant MLH1 methylation is absent. In most studies, aberrant MLH1 methylation has been detected in only a small percentage of LS colon cancers in individuals with germline mutations in MLH1.[283-286] Thus, detection of aberrantly methylated MLH1 in colon cancer is more suggestive of a sporadic MSI tumor. Since assays of methylation are complex and resource-intensive, surrogate markers of MLH1 methylation have been examined. One study found that loss of immunohistochemical staining for p16 correlated strongly with both MLH1 methylation and BRAF V600E mutations (BRAF mutations are discussed in detail in the following paragraphs). However, only 30% of sporadic tumors examined in this study exhibited loss of p16 expression, limiting the utility of this assay.
BRAF mutations have been detected predominantly in sporadic MSI tumors.[288-291] This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing. MLH1 hypermethylation and/or BRAF mutation testing are increasingly utilized in universal LS testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 mutations.
(Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for more information about the clinical role of BRAF and hypermethylation testing.)Germline MLH1 hypermethylation
Reports of patients with germline MLH1 hypermethylation should not be confused with EPCAM mutation-induced hypermethylation of MSH2, as described below. Prior paragraphs have emphasized the issues associated with the common, acquired somatic hypermethylation of the MLH1 promoter. However, examples of hypermethylation of the MLH1 promoter described in the germline have generally not been associated with a stable Mendelian inheritance.
A comprehensive review of MLH1 constitutional epigenetic alterations involving hypermethylation of one MLH1 allele has been published. Such epimutations are seen in patients with early-onset LS and/or multiple tumors of the LS type. Germline sequence variations or rearrangements are not seen in these patients, although the tumors show MSI-H, loss of MLH1 protein expression, and an absence of BRAF V600E mutations. These patients commonly have no family history of LS-like tumors. Interestingly, inheritance appears to be maternal, and therefore non-Mendelian. The constitutional monoallelic hypermethylation may appear as a mosaic, involving different tissues to a varying extent. In addition, the constitutional epimutation is typically reversible in the course of meiosis, such that offspring are usually unaffected. Because inheritance has been demonstrated in very few families, performing genetic counseling and genetic testing (which requires specialized research techniques) is particularly challenging.EPCAM/TACSTD1
Tumors with MSI and loss of MSH2 protein expression are generally indicative of an underlying MSH2 germline mutation (inferred MSH2 mutation). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter. Nevertheless, in at least 30% to 40% of these cases of inferred MSH2 mutation, no germline mutation can be detected with state-of-the-art technology. One Chinese family with tumors showing MSH2 loss was found to have allele-specific hypermethylation that appeared to have been an inherited phenomenon. Another study of a family with MSH2-deficient MSI-high tumors employed the commonly used diagnostic MLPA analysis of MSH6 and also showed reduced expression of MSH6. In doing so, a decrease in signal was observed for exon 9 of the EPCAM (TACSTD1) gene, which is near MSH2. Use of additional MLPA probes located between exon 3 of EPCAM and exon 1 of MSH2 demonstrated that the deletion spanned most 3’ exons of EPCAM, but spared the MSH2 promoter. The mutation in EPCAM was found to induce the observed methylation of the MSH2 promoter by transcription across a CpG island within the promoter region. The presence of EPCAM mutations showing similar methylation-mediated MSH2 loss was found at about the same time in families from Hungary.. On the strength of these observations, EPCAM testing has already been introduced clinically for patients with loss of MSH2 protein expression in their CRCs who lack detectable MSH2 germline mutation. One study of two families with the same EPCAM deletion found few extracolonic cancers and no endometrial cancers. However, a subsequent study demonstrated that women with MSH2 protein expression loss caused by EPCAM mutations are also at risk of endometrial cancer.IHC
A complementary and perhaps even alternative approach to MSI is to test the tumor by IHC for protein expression using monoclonal antibodies of the MSH2, MLH1, MSH6, and PMS2 proteins. Loss of expression of these proteins appears to correlate with the presence of MSI and may suggest which specific MMR gene is altered in a particular patient.[297-300]
(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about issues related to informed consent for MSI and IHC testing.)Tumor testing for suspected LS
It appears that clinical practice has shifted from reliance on MSI in the early days of tumor testing to increasing, and in many cases exclusive, reliance on IHC currently. Using both of these tests increases the sensitivity of the initial screen and improves quality assurance; therefore, many laboratories assess both MSI and IHC initially. However, because these tests are so commonly regarded as simple alternatives, cost-effectiveness considerations seem to support IHC and account for its preferential use. Part of this rationale is that the information provided by IHC may direct testing toward a specific MMR gene (the one with loss of protein expression) as opposed to comprehensive testing that would be necessitated by the use of MSI alone.[221,222,301-304] Arguments for a sequential approach to increase efficiency have been made. A German consortium has proposed an algorithm suggesting a sequential approach; this is likely to depend on the different costs of MSI and IHC and the prior probability of a mutation. Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories. To identify a more efficient screening approach, the strategy of performing IHC staining only for PMS2 and MSH6 has been considered, on the assumption that negative staining of either of these would, in most instances, detect the majority of cases of LS. This approach may be more appropriate when all tumors are being screened (universal testing). Although this strategy appears attractive from the standpoint of efficiency, staining for all four MMR proteins remains the current standard of care. Further studies are necessary to validate the utility of the two-protein approach. (Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for more information.)
Even in centers that rely exclusively on IHC testing, there may be a role for subsequent MSI testing in cases in which the clinical picture suggests LS, notwithstanding the results of IHC.
If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported [222,301,305] or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.
(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about issues related to informed consent for MSI and IHC testing.)Other techniques
In instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC, germline mutation analysis of MLH1, MSH2, and MSH6 may be considered. This approach is, however, time consuming and expensive. Strategies to screen for mutations using heteroduplex analysis-based techniques have been explored. These techniques are limited by the need to perform DNA sequencing as a subsequent step on all aberrant samples detected in screening. Additionally, such techniques frequently detect numerous variants of uncertain significance. They cannot, therefore, be recommended for routine clinical use at this time.Genetic testing
Genetic testing for germline mutations in MLH1, MSH2, MSH6, and PMS2 can help formulate appropriate intervention strategies for the affected mutation-positive individual and at-risk family members.
If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members (referred to as predictive testing). Family members who test negative for the familial mutation are generally not at increased risk of CRC or other LS-associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial mutation should follow surveillance and management guidelines for LS. (Refer to the Interventions for LS section of this summary for more information.)
If no mutation is identified in the affected family member, then testing is considered uninformative for the individual and at-risk family members. This would not exclude an inherited susceptibility to colon cancer in the family but rather could indicate that current gene testing technology is not sensitive enough to detect the mutation in the genes tested. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Mutation testing utilizing sequencing alone will not detect large genomic rearrangements in MSH2 or MLH1 that may be present in a significant number of LS probands.[308-310] An assessment of 365 probands with suspected LS showed 153 probands with germline mutations in MLH1 or MSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in MLH1 and MSH2, respectively. Such mutations can be detected by MLPA or Southern blotting (MLPA has largely replaced Southern blotting).[312,313] MLPA analysis of MLH1, MSH2, and MSH6 is commercially available and should be performed in cases in which no mutation is detected by sequence analysis.
Alternatively, the family could have a mutation in a yet-unidentified gene that causes LS or a predisposition to colon cancer. Another explanation for a negative mutation test is that, by chance, the individual tested in the family has developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case), while the other cases in the family are really the result of a germline mutation. If this scenario is suspected, testing another affected individual is recommended. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis. If no mutation can be identified in an affected family member, testing should not be offered to at-risk members. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions for LS section of this summary for more information.)DNA MMR genes
LS is caused by mutation of one of several DNA MMR genes.[314-320] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in LS include MSH2 (mutS homolog 2) on chromosome 2p22-21;[317,318] MLH1 (mutL homolog 1) on chromosome 3p21; PMS2 (postmeiotic segregation 2) on chromosome 7p22;[320,321] and MSH6 on chromosome 2p16. The genes MSH2 and MLH1 are thought to account for most mutations of the MMR genes found in LS families.[322,323]
A variety of LS-associated mutations in MSH2 and MLH1 have been identified. These include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations.[309,323-327] The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in MSH2, MLH1, MSH6, and most recently for PMS2. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for MSH2 and MLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in LS, methods such as Southern blot or MLPA, for detection of large deletions, are being used. (Refer to the Genetic/molecular testing for LS section of this summary for more information about issues to be considered in testing for these mutations.)MLH1
MLH1 and MSH2 make up the majority of LS mutations. Up to 50% of mutation-positive LS families harbor an MLH1 mutation, with some geographic variation.Genotype-phenotype correlations
MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS. The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%.[225,230,331] The lifetime risk of endometrial cancer is estimated to be approximately 40%.[3,230] Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.Practices and pitfalls in testing
In contrast to the scenario of MSI associated with loss of expression of MSH2, MSH6 or PMS2, absence of MLH1 expression is not specific to LS. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Therefore, absent MLH1 expression is less specific for LS than absence of the other MMR proteins. In addition, rare instances of inherited germline MLH1 methylation have added further complexity to the interpretation of MSI associated with absence of MLH1 expression. (Refer to the Microsatellite instability [MSI] section for more information about germline MLH1 hypermethylation.)MSH2
The prevalence of MSH2 mutations in individuals or families with LS has varied across studies. MSH2 mutations were reported in 38% to 54% of LS families in studies including large cancer registries, cohorts of early-onset CRC (<55 years), and registries around the world.[227,270]Genotype-phenotype correlations
The lifetime risk of colon cancer associated with MSH2 mutations is estimated to be between 48% and 68%.[225,230,331] In a case series of LS patients, those carrying germline MSH2 mutations (49 individuals, 45% females) had a lifetime (cutoff of age 60 years) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% females). In addition, the same group reported a significantly higher prevalence of poorly differentiated CRCs (44% for MSH2 carriers vs. 14% for MLH1 carriers; P = .002) and Crohn-like reaction (49% for MSH2 carriers vs. 27% for MLH1 carriers; P = .049). Another study reported no significant differences between the prevalence of colorectal and extracolonic cancers in 22 families with germline MLH1 mutations and in 12 families with germline MSH2 mutations.
Multiple groups have reported that MSH2 and MSH6 carriers have a greater chance of presenting with endometrial cancers before CRCs than do MLH1 carriers.[3,262,334] The average age at diagnosis of endometrial cancers differed with genotype in two studies: age 41 years for MSH2 , age 49 years for MLH1, and age 55 years for MSH6 carriers.[335,336] In contrast with early data indicating no increased risk of endometrial cancer, a 2011 study suggests that there may be an increased risk in patients with EPCAM mutations.Practices and pitfalls in testing
In patients with absence of MSH2 and MSH6 protein expression who have undergone genetic testing with no mutation found by the currently available standard techniques, germline mutation testing for EPCAM/TACSTD1 should be considered. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 mutation identified will have germline deletions in EPCAM/TACSTD1. The latter mechanism accounts for approximately 5% of all LS cases. (Refer to the EPCAM/TACSTD1 section of this summary for more information.)MSH6
Most series show a prevalence of germline MSH6 mutations in approximately 10% of LS families. However, the reported range (5%–52%) is large.[262,265,266,338-341] This wide variation is likely a result of small sample sizes, referral bias, and ascertainment bias.Genotype-phenotype correlations
The lifetime risk of colon cancer associated with MSH6 mutations is estimated to be between 12% and 22%.[228,230] The lifetime risk of CRC might be lower in MSH6 carriers than in MSH2 and MLH1 carriers. Initial studies have suggested that inactivating germline mutations of MSH6 might be more frequent in persons with a later average age at onset of CRC whose tumors exhibit a non-MSI-H phenotype.
One study reported on 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating mutations in MSH6. While the prevalence of CRCs by age 70 years was not significantly different between MSH6 and MLH1 or MSH2 carriers (P = .0854), the mean age at diagnosis for colorectal carcinoma in male MSH6 mutation carriers was 55 years (n = 21; range, 26–84 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively. The prevalence of CRC was significantly lower in women with MSH6 germline mutations than in MLH1 or MSH2 carriers (P = .0049). The mean age at diagnosis for colorectal carcinoma in female MSH6 mutation carriers was 57 years (n = 15; range, 41–81 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively.
In addition, endometrial cancer has been reported to be more common in MSH6 families. In the same study, the cumulative risk of uterine cancer was significantly higher in MSH6 mutation carriers (71%) than in MLH1 (27%) and MSH2 (40%) mutation carriers (P = .02). The mean age at diagnosis of endometrial carcinoma was 54 years in MSH6 mutation carriers (n = 29; range, 43–65 years) versus 48 years and 49 years in MLH1 and MSH2 mutation carriers, respectively. A group of researchers reported on ten MSH6 kindreds with LS in which 70% of females had been diagnosed with endometrial cancer compared with 31% and 29% in MLH1 and MSH2 carriers, respectively. One study found the prevalence of endometrial carcinoma to be 58% in 12 MSH6 families with a mean age at diagnosis of 57 years.
One group of researchers assembled the largest series of MSH6 mutation carrier families to estimate penetrance of cancers. A total of 113 families of MSH6 mutation carriers from five countries were ascertained through family cancer clinics and population-based cancer registries. The families contained an estimated 1,043 mutation carriers. By age 70 years, 22% (95% CI, 14%–32%) of male MSH6 mutation carriers developed CRC compared with 10% (95% CI, 5%–17%) of female MSH6 mutation carriers. By age 80 years, 44% (95% CI, 28%–62%) of male MSH6 mutation carriers were diagnosed with CRC, compared with 20% (95% CI, 11%–35%) of female MSH6 mutation carriers. For all MSH6 mutation carriers, the increased risk of CRC, relative to that of the general population, across all age groups was statistically significantly elevated (HR, 7.6; 95% CI, 5.4–10.8; P < .001). By ages 70 years and 80 years, 26% (95% CI, 18%–36%) and 44% (95% CI, 30%–58%), respectively, of women would be diagnosed with endometrial cancer. Female MSH6 mutation carriers had an endometrial cancer risk that was about 25 times higher than women in the general population (HR, 25.5; 95% CI, 16.8–38.7; P < .001).
In the same study, female MSH6 mutation carriers had a cumulative risk of other Lynch cancers (i.e., ovarian, stomach, small intestine, kidney, ureter, or brain) of 11% (95% CI, 6%–19%) by age 70 years and 22% (95% CI, 12%–38%) by age 80 years. The risk of LS cancers, excluding colorectal and endometrial cancers, was six times that of the general population (HR, 6.0; 95% CI, 3.4–10.7; P < .001). Male MSH6 mutation carriers showed no evidence of an increased risk of these cancers (HR, 0.8; 95% CI, 0.1–8.8; P = .9). The authors estimated that 24% (95% CI, 16%–37%) of men and 40% (95% CI, 32%–52%) of women harboring deleterious MSH6 mutations would be diagnosed with any LS cancer by age 70 years and that these values will increase to 47% (95% CI, 2%– 66%) of men and 65% (95% CI, 53%–78%) of women by age 80 years.Practices and pitfalls in testing
One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.
MSH6 colorectal tumors can be MSI-H, MSI-L, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-H phenotype. Of the 16 endometrial tumors tested, 11 were MSI-H (69%); four were MSI-L (25%), and one was MSS (6%).PMS2
The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available.[343-345] One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS. A population-based study reported a prevalence of approximately 5% (1 of 18).Genotype-phenotype correlations
A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.
In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.Polymorphisms in Unrelated Genes Affecting Expression in LS
Polymorphisms potentially affecting expression in MMR genes fall into two categories: those whose mechanisms are already suspected to have an effect on cancer-related pathways, and those that are truly anonymous. Several candidate genes have been studied. Anonymous genes have also been evaluated.
Studies have demonstrated that a polymorphism in the promoter region of the insulin-like growth factor 1 (IGF1) gene modifies age of onset of CRC in LS.[347,348]. The polymorphism is a variable number of CA-dinucleotide repeats approximately 1 kb upstream of the transcription start site of IGF1. There is significant variability between individuals and populations with respect to repeat length. Carriers of shorter repeat lengths (shortest allele ≤17 repeats) develop CRC on average 12 years earlier than those with longer repeat lengths. It is unclear whether this polymorphism influences extracolonic malignancies. Additionally, the cyclin D1 polymorphism G870A may be associated with earlier age of onset of CRC in LS,[349,350] although the association appears to be more reproducible in MSH2 mutation carriers than in MLH1 mutation carriers.[350,351]
Two single nucleotide polymorphisms (SNPs) identified in genome-wide association studies have been reported to increase CRC risk in MMR gene mutation carriers. (Refer to the Genome-wide searches section of this summary for more information.) Having the C-allele of either SNP increased the risk of CRC in a dose-dependent fashion (with homozygotes at a higher risk than heterozygotes). The first SNP in 8q23.3 increased CRC risk 2.16-fold for homozygote carriers of the SNP. The second SNP, located in 11q23.1, increased CRC risk only in female SNP carriers by 3.08 for homozygotes and 1.49 for heterozygote SNP carriers.
In a study of 684 mutation carriers from 298 Australian and Polish families, nine SNPs within six previous CRC susceptibility loci were genotyped to investigate their potential as modifiers of disease risk in LS. Two SNPs, rs3802842 (11q23.1) and rs16892766 (8q23.3), were associated with CRC susceptibility in MLH1 mutation–positive LS patients. However, a subsequent study of 748 French MMR mutation carriers did not replicate the association between the IGF1 CA repeat and age of CRC onset or the association between SNPs in 8q23.3 and 11q23.1 and CRC risk.
Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.Diagnostic strategies for all individuals diagnosed with CRC (universal testing)
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making?[355,356] The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:[355,356]
- All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.
- All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.
The EGAPP analysis made several assumptions, including (1) IHC and MSI will not detect all LS patients and (2) not all patients with CRC will opt for testing.
Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify LS among persons with newly diagnosed CRC. The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline mutation testing followed by directed screening and risk-reducing surgery. Similar to the EGAPP working group, IHC followed by BRAF mutation testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life year gained resulted from this strategy. In this model, the number of relatives tested (3 to 4) per proband was a critical determinant of both effectiveness and cost-effectiveness.
A different approach based on risk assessments of 100,000 simulated individuals representative of the U.S. population who were tracked from age 20 and exposed to 20 different screening strategies has been reported. In this study, the strategies involved risk assessment at different ages utilizing the PREMM126 model followed by mutation analysis for MLH1, MSH2, MSH6, and PMS2 in individuals whose mutation risk threshold exceeded 0%, 2.5%, 5%, or 10%. In individuals whose risk assessment (starting at age 25, 30, or 35 years) for carrying a mutation exceeded 5%, colorectal and endometrial cancers in mutation carriers were reduced by 12.4% and 8.8%, respectively. In the whole population, this strategy increased the quality adjusted life-years by 135 years per 100,000 individuals with an average cost-effectiveness ratio of $26,000. The authors suggested that the outlined strategy was more cost effective than current practice and could improve health care outcomes.
Recognizing the controversial conclusions of the EGAPP working group, the Centers for Disease Control and Prevention convened a special meeting of cancer genetics experts to critique these recommendations. The group concluded that “genetic screening of all newly diagnosed CRC cases for LS (universal LS screening) can theoretically result in population health benefits, and feasibility has been demonstrated."Universal MSI/IHC colorectal cancer screening in clinical practice
Universal screening has been adopted by many institutions in recent years. A 2011 survey of the National Society of Genetic Counselors revealed that more than 25% of respondents had some form of universal screening implemented at their center. Tumor screening methods varied; 34 of 53 (64.2%) started with IHC, 11 of 53 (20.8%) started with MSI testing, and 8 of 53 (15.1%) performed both tests on newly diagnosed colorectal tumors. A 2012 survey suggested that some form of universal screening was being routinely performed at 71% of the National Cancer Institute (NCI) comprehensive cancer centers but that utilization dropped to 15% among a random sample of community hospital cancer programs. NCCN 2014 guidelines support IHC testing of all CRCs diagnosed in patients younger than 70 years if tumor is available and in patients 70 years or older if they meet Bethesda guidelines. Universal screening in all individuals irrespective of age was associated with a doubling of incremental cost per life-year saved compared with screening only those younger than 70 years. The authors of this analysis conclude that screening individuals younger than 70 years appears reasonable, while screening all individuals regardless of age might also be acceptable, depending on societies' willingness to pay.
Several studies have demonstrated the feasibility and usefulness of universal screening for LS. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 (2.8%) patients had LS. For each proband, an average of three additional family members were subsequently diagnosed with LS. A subsequent pooled analysis of 10,206 incident CRC patients tested with MSI/IHC as part of four large studies revealed a mutation detection rate of 3.1%. This study compared four strategies for tumor testing for the diagnosis of LS. The strategy of tumor testing all individuals diagnosed with CRC at age 70 years or younger and testing older individuals who met one of the revised Bethesda guidelines yielded a sensitivity of 95.1%, a specificity of 95.5%, and a diagnostic yield of 2.1%. This strategy missed 4.9% of LS cases, but 34.8% fewer cases required IHC/MSI testing, and 28.6% fewer cases underwent germline testing than in the universal approach.
An important implication of universal screening for LS is the reality that it does not result in automatic germline testing in appropriate individuals. Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. In addition, patient consent and compliance with subsequent testing may significantly influence uptake of genetic counseling. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF mutation–negative) ultimately consented to and proceeded with germline MMR testing. One institution found 21 deleterious mutations among 1,100 patients who underwent routine MSI and IHC testing after a diagnosis of CRC. This study found markedly increased uptake of genetic counseling and germline MMR gene testing when both the surgeon and a genetic counselor received a copy of abnormal MSI/IHC results, especially when the genetic counselor played an active role in patient follow-up.
To simplify the process of IHC testing and to help decrease cost, a strategy that employs IHC testing for PMS2 and MSH6 alone has been suggested. This strategy relies on the binding properties of the MMR heterodimer complexes, by which gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6, respectively, but the converse is not true. The authors do not suggest a definitive algorithm after the finding of an IHC-deficient tumor. However, given the predominance of MLH1 and MSH2 mutations in LS, the authors suggest that a PMS2-deficient tumor should be investigated for either MLH1 hypermethylation (utilizing BRAF mutations status as a proxy) or germline MLH1 mutation analysis. Similarly, MSH6 deficiency would generally result in MSH2 germline testing as a first step. This strategy has not been validated or widely adopted in clinical practice.
There is an ongoing discussion about best practices for the informed consent process for this tumor testing. Identification of genetic predisposition to cancer generally mandates explicit informed consent because of concerns for the possibility of insurance discrimination (irrespective of the Genetic Information Nondiscrimination Act of 2008), adverse psychological outcomes, and costs associated with further testing.[366,367] The EGAPP working group specifically recommends obtaining informed consent for MSI or IHC testing. Nevertheless, debate about this issue continues, partially because of pragmatic concerns surrounding the feasibility of obtaining such consent before the procedure. One proposed approach suggests a preparatory conversation informing patients before their procedure that CRC runs in families and that if their tumor has features characteristic of a heritable type, they will be contacted by a genetic health care provider for further assessment of the genetic basis of their cancer. A cross-sectional survey of U.S. cancer programs (20 NCI–designated comprehensive cancer centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathologic evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent before tumor testing.Diagnostic strategies for all individuals diagnosed with endometrial cancer
Based on a Markov mathematical model, a strategy of performing IHC for MMR protein expression in all patients with endometrial cancer, irrespective of the age at diagnosis, who have a first-degree relative with endometrial cancer, was reported to be cost-effective in the detection of LS in patients with LS-related cancer. (Refer to the Genetic testing section of this summary for more information about performing IHC for MMR protein expression.) In this study, incremental cost-effectiveness ratio was defined as the additional cost of a specific strategy divided by its health benefit compared with an alternative strategy. In this model, the strategy of performing IHC on the tumor from all patients diagnosed with LS-related cancer who have a first-degree relative with endometrial cancer had an incremental cost ratio of $9,126 per year of life gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer younger than 50 years with at least one first-degree relative with LS-related cancer.
The model predicted that if all endometrial cancers in the United States (estimated to be 45,000 new cases in 2010) underwent IHC screening, 827 women (1.84%) would be diagnosed as LS patients. However, applying the strategy of testing only those endometrial tumors of patients with at least a first-degree relative with LS-related cancer, 755 affected individuals (1.68%) would be identified. If the Amsterdam II criteria were applied, 539 carriers (1.2%) would be identified. The authors stated that the incremental benefit of the most cost-effective strategy was associated with an average life expectancy gain of only 1 day compared with testing by Amsterdam II criteria. However, they argue that this may be significant, as it is comparable to the life expectancy gain from triennial cervical cancer screening, which is a current recommendation from the American College of Obstetricians and Gynecologists for women older than 30 years in the general population.Interventions for LS
Several aspects of the biologic behavior of LS suggest how the approach to surveillance should differ from that for average-risk people:
- CRCs in LS occur earlier in life than do sporadic cancers. For MLH1 and MSH2 mutation carriers, the estimated risk of CRC at age 40 years is 31% for females and 32% for males; at age 50 years, the estimated risks are 52% and 57%, respectively. This suggests that screening should begin earlier in life.
- A larger proportion of LS CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Annual colonoscopic surveillance is recommended.
- The progression from normal mucosa to adenoma to cancer is accelerated,[370,371] suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy.[371,372] Because patients with LS have an ordinary, or slightly increased, frequency of polyps but a substantially increased rate of cancer, it is clear that a larger proportion of polyps progress to cancer. It has been demonstrated that MMR gene mutation carriers develop adenomas at an earlier age than noncarriers. The mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 years), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 years).
- Incidence of CRC throughout life is substantially higher, suggesting that the most sensitive test available should be used.
- Patients with LS are at an increased risk of other cancers, especially those of the endometrium and ovary. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population. There is some evidence that the rate of individual cancers varies from kindred to kindred.[240,373,374] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.
Evidence-based reviews of surveillance colonoscopy in LS have been reported.[376,377] There is only one controlled trial of CRC screening in LS.[371,372] In a study from Finland, 252 at-risk members of 22 families with LS were offered screening for 15 years. One hundred thirty-three individuals accepted screening by either colonoscopy or barium enema and sigmoidoscopy, and 123 of the at-risk members (93%) completed screening. One hundred nineteen did not accept advice to be screened, although 24 (20%) had screening examinations outside the study. Once genetic testing was performed in these families (starting in 1996, 14 years after the beginning of screening), screening was recommended for mutation-positive controls, 63% of whom chose to begin active screening. The screened group had 62% fewer cancers (P < .03) and 65% fewer CRC deaths (10 vs. 26, P = .003). All of the CRCs detected in the screened population were local and caused no deaths, compared with nine deaths from CRC in the control group. The results, while biologically plausible, are of limited validity, primarily because the main comparison was between compliant and noncompliant patients, and compliant patients have been shown to have an inherently better prognosis, independent of intervention. This assertion is supported by the observed low rates of all causes of mortality. It is noteworthy, however, that these differences were observed in spite of the fact that most mutation-positive controls ultimately entered a screening program.
The data from this Finnish trial were subsequently updated. Over the course of the study (early 1980s to present), the approach to colonoscopy surveillance has evolved. Colonoscopy was the approach used for MMR mutation carriers when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The series limited its attention to subjects with no prior diagnosis of adenoma or cancer. The 420 mutation carriers, at a mean age of 36 years, underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors concluded by recommending surveillance at 2-year intervals. The appropriate colonoscopy surveillance interval remains every 1 to 2 years according to most consensus guidelines (see Table 11). Analysis of surveillance data in 242 patients 10 years after mutation testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with mutation-negative relatives. However, this may be attributable to the modest sample size of the study.
In other series, the risk of developing adenomas in an MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers. By age 60 years, 70% of the carriers developed adenomas, compared with 20% of noncarriers. As previously mentioned, these mutation carriers developed adenomas at an earlier age than noncarriers. Most of the adenomas in carriers had absence of MMR protein expression and were more likely to have dysplastic features, compared with adenomas from control subjects. Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.[381,382]
Although screening the intact colon is usually recommended for at-risk LS family members, some patients, faced with the high risk of CRC and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.
Table 11 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for LS.Table 11. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndrome
|Organization||Tumor MSI||Tumor IHC||MMR/EPCAM Genetic Testing||Age Screening Initiated||Frequency||Method||Comments|
|American Society of Colon and Rectal Surgeons (2001, 2003) [140-142]||Yes||Yes||MMR: Yes||NA||NA||NA|
|American Cancer Society (2002) ||NA||NA||MMR: Counseling to consider genetic testing||21 y||1–2 y until age 40 y, then annually||C|
|GI Societies (2003)a ||NA||NA||MMR: NA||20–25 y||1–2 y||C|
|Europe Mallorca Group (2007) ||Yes||Yes||MMR: Yes||20–25 y; consider stopping at age 80 y||1–2 y||C||Despite acknowledging that existing data support a 3-y screening interval, this group elected to recommend a shorter screening interval.|
|NCCN (2014) ||Yes||Yes||MMR: Yes||20–25 y OR 2–5 y before the youngest age at diagnosis in the family if it is before age 25 y, whichever comes first||1–2 y||C||Additional recommendations for families in whom a tumor has shown informative IHC and MSI, but no germline mutation found. Refer to page LS-A-2 of the NCCN guidelines for more information.|
|C = colonoscopy; GI = gastrointestinal; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; NA = not addressed; NCCN = National Comprehensive Cancer Network.|
|aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.|
Chemoprevention in LS
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with LS who were in surveillance programs at a number of international centers. The study randomly assigned 861 participants to aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range: 1–128 mo), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (because of an aspirin sensitivity or a history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intention-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all LS cancers (endometrial, ovarian, pancreatic, small bowel, gall bladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in LS patients. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 LS patients enrolled in the study were published in 2008  and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (relative risk [RR], 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range: 7–74 mo). The CAPP3 trial, which will evaluate the effect of lower doses of aspirin, is expected to begin in 2013.Screening for endometrial cancer in LS families
Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.
Cancer of the endometrium is the second most common cancer observed in LS families with initial estimates of cumulative risk in LS carriers of 30% to 39% by age 70 years.[240,242] In a large Finnish study of 293 putative LS gene carriers, the cumulative lifetime risk of endometrial cancer was 43%. Endometrial cancer risk was directly related to age, ranging from 3.7% at age 40 years to 42.6% by age 80 years, compared with a 3% endometrial cancer risk in the general population. The maximal risk of endometrial cancer in LS families occurs 15 years earlier than in the general population, with the highest risk occurring between ages 55 and 65 years. In a community study of unselected endometrial cancer patients in central Ohio, at least 1.8% (95% CI, 0.9%–3.5%) of newly diagnosed patients had LS. Adenocarcinomas of the lower uterine segment may carry a greater risk of manifesting LS.
In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. An office endometrial sampling, or a dilatation and curettage (D&C), is then performed, providing a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with symptoms of stage I disease. There are no data suggesting the clinical presentation in women with LS differs from the general population.
Given their substantial increased risk of endometrial cancer, endometrial screening for women with LS has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. Although the Pap test occasionally leads to a diagnosis of endometrial cancer, the sensitivity is too low for it to be a useful screening test. The presence of endometrial cells in a Pap smear obtained from a postmenopausal woman not taking hormone replacement therapy is abnormal and warrants further investigation.[389,390] Two studies have examined the use of TVUS in endometrial screening for women with LS.[391,392] In one study of 292 women from LS or LS-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women. In a second study, 41 women with LS were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer. Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with LS, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity over TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS. While this cohort study demonstrates that endometrial sampling may have benefits over TVUS for endometrial screening, there are no data that predict screening with any other modality has benefits for endometrial cancer survival in women with LS. Given the favorable survival for endometrial cancer diagnosed by symptoms, it is unlikely that a sufficiently powered screening study will be able to demonstrate a survival advantage. Certainly, women with LS should be counseled that abnormal or postmenopausal vaginal bleeding warrants an endometrial sampling or D&C.
Routine screening for endometrial cancer has not been shown to be beneficial in the general population, but expert consensus suggests that it be considered in women who are members of high-risk LS families. Some studies suggest that women with a clinical or genetic diagnosis of LS do not universally adopt intensive gynecologic screening.[394,395] (Refer to the Gynecologic cancer screening in LS section of this summary for more information.) Despite absence of a survival advantage, a task force organized by NIH has suggested annual endometrial sampling beginning at age 30 to 35 years. TVUS can also be considered annually to evaluate the ovaries.[377,384]
The published literature on TVUS for endometrial cancer screening has shown it to be insensitive and nonspecific, but because there may still be a role for TVUS in ovarian cancer screening, clinical practice guidelines have been reluctant to date to recommend against TVUS.Surgical management in LS
One of the hallmarks of LS is the presence of synchronous and metachronous CRCs. The incidence of metachronous CRCs has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy. Because of the increased incidence of synchronous and metachronous neoplasms, the treatment of choice for a patient with LS with neoplastic lesions in the colon is generally an extended colectomy (total or subtotal). Nevertheless, treatment has to be individualized. Mathematical models suggest that there are minimal benefits of extended procedures in individuals older than 67 years, compared with the benefits seen in younger individuals with early-onset cancer. In one Markov decision analysis model, the survival advantage for a young individual with early-onset CRC undergoing an extended procedure could be up to 4 years longer than that seen in the same individual undergoing a segmental resection. The recommendation for an extended procedure must be balanced with the comorbidities of the patient, the clinical stage of the disease, the wishes of the patient, and surgical expertise. No prospective or retrospective study has shown a survival advantage for patients with LS who underwent an extended resection versus a segmental procedure. Two studies have shown that patients who undergo extended procedures have fewer metachronous CRCs and additional surgical procedures related to CRC than do patients who undergo segmental resections.[396,398] Balancing functional results of an extended procedure versus a segmental procedure is of paramount importance. Although the majority of patients adapt well after an abdominal colectomy, some patients will require antidiarrheal medication. A decision model compared quality-adjusted life years (QALYs) for a 30-year-old patient undergoing an abdominal colectomy versus a segmental colectomy. In this model, there was not much difference between the extended and segmental procedure, with QALYs being 0.3 years more in patients undergoing a segmental procedure than in those undergoing an extended procedure.
When considering surgical options, it is important to recognize that a subtotal or total colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant after an abdominal colectomy has been reported to be 12% at 12 years post-colectomy. In addition to the general complications of surgery, there are the potential risks of urinary and sexual dysfunction and diarrhea after an extended colectomy, with these risks being greater the more distal the anastomosis. Therefore, the choice of surgery must be made on an individual basis by the surgeon and the patient.
In patients with LS and rectal cancer, similar surgical options (extended vs. segmental resection) and considerations must be given. Extended procedures include restorative proctocolectomy and IPAA if the sphincter can be saved or proctocolectomy with loop ileostomy if the sphincter cannot be saved. Two retrospectives studies reported a 15% and 18% incidence of metachronous colon cancer after segmental rectal cancer–resection in patients with LS.[400,401] In one of the studies, the combined risk of metachronous high-risk adenomas and cancers was 51% at a median follow-up of 101.7 months after proctectomy.
There are no data about fertility in LS patients based on type of surgery. In FAP patients, no difference in fecundity after abdominal colectomy and IRA has been reported, whereas there is a 54% decrease in fecundity in patients who undergo restorative proctocolectomy with ileal pouch anastomosis compared with the general population.
Most clinicians who treat patients with LS will favor an extended procedure at the time of CRC diagnosis. However, as stated above, the choice of surgery must be made on an individual basis by the surgeon and the patient. The topic of surgical management in LS has been summarized in the following reviews.[403-405]Advances in Endoscopic Imaging in Hereditary CRC
Performance of endoscopic therapies for adenomas in FAP and LS, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and LS the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in LS.Chromoendoscopy
The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in AFAP, and subtle flat adenomas in LS. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[381,406-411] with or without magnification, or possibly newer imaging techniques such as narrow-band imaging, may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper gastrointestinal endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.
In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma. Some of these studies involved tandem procedures—white-light exam followed by randomization to “intensive” (> 20-minute pull-back from cecum) inspection versus chromoendoscopy—with significantly more adenomas detected in the chromoendoscopy group. However, in several randomized trials, no significant difference in yield was seen.[415,416]
In a randomized trial of subjects with LS, standard colonoscopy, with polypectomy as indicated, was followed by either indigo carmine chromoendoscopy or repeat “intensive” white-light colonoscopy (a design very nearly identical to the average-risk screening group noted above). In this series, no significant difference in adenoma yield between the chromoendoscopy and intensive white-light groups was detected. However, these patients were younger and in many cases had undergone several previous exams that might have resulted in polyp clearing.
In a German study, one series of LS patients underwent white-light exam followed by chromoendoscopy, while a second series underwent colonoscopy with narrow-band imaging followed by chromoendoscopy. Significant differences in flat polyp detection favored chromoendoscopy in both series, although some of the detected lesions were hyperplastic. In a French series of LS subjects that also employed white-light exam followed by chromoendoscopy, significantly more adenomas were detected with chromoendoscopy.
Fewer evaluations of chromoendoscopy have been performed in attenuated FAP than in LS. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination. All had more than 1,000 diminutive adenomas found on chromoendoscopy, in agreement with pathology evaluation after colectomy.
A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.Small bowel imaging
Patients with PJS and juvenile polyposis syndrome are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in LS, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in LS.
Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine for more precise imaging. None of these measures were sensitive for small lesions. Any therapeutic undertaking required laparotomy. This entailed resection in most cases, although intraoperative endoscopy, with or without enterotomy for scope access, has been available for many years. Peroral enteroscopy (aided by stiffening overtubes with two balloons, one balloon, or spiral ribs) has been employed to overcome the technical problem of excessive looping, enabling deep jejunal access with therapeutic (polypectomy) potential.
Most data relate that PJS with double-balloon enteroscopy is the preferred method for endoscopy of the small bowel. This may involve only peroral enteroscopy, although subsequent retrograde enteroscopy has been described for more complete evaluation of the total small bowel. Because these procedures are time-consuming and involve some risk of complication, deep enteroscopy is usually preceded by more noninvasive imaging, including traditional barium exams, capsule endoscopy, and CT or magnetic resonance enterography.
In FAP, data from capsule endoscopy  show a 50% to 100% prevalence of jejunal and/or ileal polyps in patients with Spigelman stage III or stage IV duodenal involvement but virtually no such polyps in Spigelman stage I or stage II disease. All polyps were smaller than 10 mm and were not biopsied or removed. Consequently, their clinical significance remains uncertain but is likely limited, given the infrequency of jejunoileal cancer reports in FAP.
Capsule endoscopy in the small series of PJS patients described above  showed the presence of a similar frequency (50%–100%) of polyps, but the prevalent polyps were much larger than in FAP, were more likely to become symptomatic, and warranted endoscopic or surgical excision. Capsule studies were suggested as an appropriate replacement for radiographic studies because of the sensitivity of capsule.Familial CRC
An estimated 7% to 10% of people have a first-degree relative with CRC,[422,423] and approximately twice that many have either a first-degree or a second-degree relative with CRC.[423,424] A simple family history of CRC (defined as one or more close relatives with CRC in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of CRC in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., first-degree relatives), and whether cancers have occurred across generations.[422,425] A positive family history of CRC appears to increase the risk of CRC earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals. The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that CRC in people with one affected first-degree relative is more likely to be proximal or is more rapidly progressive.
A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps  and increases the risk of CRC in relatives. The RR of CRC, adjusted for the year of birth and sex, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, with a parental history of CRC.
While familial clusters account for approximately 20% of all CRC cases in developed countries, the rare and highly penetrant Mendelian CRC diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial CRCs.
The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers. The twins included in the study all resided in their respective countries of origin into adulthood (>50 years). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.
The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 CRCs in offspring and their parents, respectively, from 1991 to 2000. The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. The overall SIR for cancers of the colon, rectum, and colon and rectum combined in the offspring of an affected parent was 1.81 (95% CI, 1.62–2.02), 1.74 (95% CI, 1.53–1.96), and 1.78 (95% CI, 1.53–1.96), respectively. The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.
Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[422,423,425-427,431-436] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for LS. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families, with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas. A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2. A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.Familial colorectal cancer type X (FCCX)
Families meeting Amsterdam-I criteria for LS who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic LS and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCCX,[217,440-444] and it has been suggested that these families be classified as a distinct group.
The genetic etiology of FCCX remains unclear. Utilizing whole-genome linkage analysis and exome sequencing, a truncating mutation in ribosomal protein S20 (RPS20), a ribosomal protein gene, was identified in four individuals with CRC from an FCCX family. The mutation cosegregated with CRC in the family, with a logarithm of the odds score of 3. Additionally, the mutation was not identified in 292 controls. No LOH was observed in tumor samples, and in vitro analyses of mature RNA formation confirmed a model of haploinsufficiency for RPS20. No germline mutations in RPS20 where found in 25 additional FCCX families studied, suggesting RPS20 mutations are an infrequent cause of FCCX. The same group had previously identified variants in the bone morphogenetic protein receptor type 1A (BMPR1A) gene in affected individuals from 2 of 18 families with FCCX. Additional studies are necessary to definitively confirm or refute a role for RPS20 or BMPR1A in FCCX.
Age of CRC onset in LS ranges from 44 years (registry series) to a mean of 52 years (population-based series).[221-223] There are no corresponding population-based data for FCCX because FCCX by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between FCCX and LS have suggested that the age of onset is slightly older in FCCX,[217,440,442] but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (type X families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (LS families). The risk of extracolonic tumors was also not found to be elevated for the type X families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within type X families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those from families with LS.Interventions for family history of CRC
There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts, if they accept that average-risk people should be screened starting at age 50 years, suggest that screening should begin earlier in life (e.g., at age 35 to 40 years) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.
A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of CRC.
These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC. These guidelines have been endorsed by a number of other organizations.
The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[138,446-449] These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this grouping, it is beyond the scope of this more targeted discussion of major gene conditions.Rare Colon Cancer Syndromes
PTEN hamartoma tumor syndromes (including Cowden syndrome)
Cowden syndrome and Bannayan-Riley-Ruvalcaba Syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN. In addition, PTEN mutations have been identified in patients with very diverse clinical phenotypes. The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN mutation, irrespective of clinical presentation.
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine and serine and threonine. Mutations of PTEN are diverse, including nonsense, missense, frameshift, and splice-variant mutations. Approximately 40% of mutations are found in exon 5, which represents the phosphate core motif, and several recurrent mutations have been observed. Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[454,455] These included pathognomonic critieria consisting of certain mucocutaneous manifestations and adult onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria have been suggested based on a systematic review. Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multi-gene cancer panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTEN mutations who do not meet these criteria. Until then, there remains ambiguity as to whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing.
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia. The vast majority of individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN mutations. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk (see Table ), melanoma, kidney cancer, and colorectal cancer should be considered part of the cancer spectra arising from germline PTEN mutations. A second study of approximately 100 patients with a germline PTEN mutation confirmed these findings and suggested a cumulative cancer risk of 85% by the age of 70 years. The age-adjusted risk of CRC was increased in mutation carriers in both studies (SIR, 5.7–10.3).[457,458] In addition, one study found that 93% of individuals with PTEN mutations who had undergone at least one colonoscopy had polyps. The most common histology was hyperplastic, although adenomas and sessile serrated polyps were also observed. The increased risk of CRC among PTEN mutation carriers has led to the recommendation of surveillance colonoscopy in these patients.[458,459] However, both the age at which to begin (30–40 y) and the subsequent frequency of colonoscopies (biennial to every 3–5 y) vary considerably and are based on expert opinion.Table 12. Cancer Risk in Individuals with Germline PTEN Mutationsa
|Cancer||Age-Adjusted SIR (95% CI)||Age-Related Penetrance Estimates|
|Breast||25.4 (19.8–32.0)||85% starting around age 30 yb|
|Colorectal||10.3 (5.6-17.4)||9% starting around age 40 y|
|Endometrial||42.9 (28.1–62.8)||28% starting around age 25 y|
|Kidney||30.6 (17.8–49.4)||34% starting around age 40 y|
|Melanoma||8.5 (4.1–15.6)||6% with earliest age of onset 3 y|
|Thyroid||51.1 (38.1–67.1)||35% at birth and throughout life|
|CI = confidence interval; SIR = standardized incidence ratio.|
|aAdapted from Tan et al. |
|bOther historical studies have suggested a lower lifetime risk of breast cancer, in the range of 25%–50%. (Refer to the Cowden syndrome section in the PDQ summary on Genetics of Breast and Ovarian Cancer summary for more information.)|
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[460-462] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[463-467] The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [6,468,469] and 21% for ovarian cancer. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS. Table 13 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.
Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix. In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors; although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.Table 13. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea
|Site||Age (y)||Cumulative Risk (%)b||Reference(s)|
|GI = gastrointestinal.|
|aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology , copyright 2010.|
|bAll cumulative risks were increased compared with the general population (P < .05), with the exception of cervix and testes.|
|cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.|
|dWesterman et al.: GI cancer does not include pancreatic cancer.|
|eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.|
PJS is caused by mutations in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[464,465] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (loss of heterozygosity [LOH]) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[475,476] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS. Subsequently, the cancers that develop in STK11 +/- mice do show LOH; indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.
Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions.[6,463] Approximately 85% of mutations are localized to regions of the kinase domain of the expressed protein, and no germline mutations have been reported in exon 9. No strong genotype-phenotype correlations have been identified.
STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS.[463,470,480] Given the results of these studies, it is unlikely that other major genes cause PJS.Juvenile polyposis syndrome (JPS)
JPS is a genetically heterogeneous, rare, childhood- to early adult-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract, although colorectal polyps predominate. JPS can present with diarrhea, GI tract hemorrhage, protein-losing enteropathy, and prolapsing polyps.[481-483] JPS is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, often in the setting of a family history of JPS. The diagnosis of a juvenile polyp is based on its histologic appearance, rather than age at onset. Solitary juvenile polyps of the colon or rectum are seen sporadically in infants and young children and do not imply a diagnosis of JPS. A clinical diagnosis of JPS is met by individuals fulfilling one or more of the following criteria:
- More than five juvenile polyps of the colon or rectum.
- Juvenile polyps in other parts of the GI tract.
- Any number of juvenile polyps and a positive family history of JPS.
JPS is caused by germline mutations in the SMAD4 gene, also known as MADH4/DPC4, at chromosome 18q21  in approximately 15% to 60% of cases, and by mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[486,487] Genotype/phenotype correlations suggest SMAD4 mutations may be associated with a greater risk of severe gastric polyposis and features of hereditary hemorrhagic telangiectasia (HHT) (see below). The lifetime CRC risk in JPS has been reported to be 39%. There appears to be an increased risk of gastric cancer, albeit much lower than the risk of CRC. Cardiac valvular abnormalities were present in 12% of individuals with JPS who were followed through a single-institution based polyposis registry, and all those with identifiable mutations had SMAD4 mutations.
JPS patients may also have signs and symptoms of HHT, such as arteriovenous malformations, mucocutaneous telangiectasias, digital clubbing, osteoarthropathy, hepatic arteriovenous malformations, and cerebellar cavernous hemangioma, suggesting that the two syndromes overlap. Most HHT patients will have a mutation in the activin receptor-like kinase 1 (ALK1) gene or in the endoglin (ENG) gene, but SMAD4 mutations have also been reported, although they are quite rare (approximately 1%–2% of patients with HHT). In one series, 3 of 30 patients (10%) with HHT without a clinical diagnosis of JPS were found to have germline mutations in SMAD4. Conversely, features of HHT were noted in 21% to 22% of SMAD4 mutation carriers in two studies of individuals with a clinical diagnosis of JPS.[481,492] In a study of 21 SMAD4 mutation carriers from nine JPS families, 81% (17 of 21) of patients had HHT manifestations. The high prevalence in this study may have been a result of the inclusion of several relatives from a single family and the inclusion of several families with the same mutation.
Surveillance for HHT has been suggested in JPS patients with germline SMAD4 mutations.[481,493] On the other hand, patients with HHT without germline mutations in ALK1 or ENG may be considered for SMAD4 germline genetic testing; the GI tract should be evaluated if a SMAD4 germline mutation is confirmed. (Refer to Table 15, Published Recommendations for Diagnosis and Surveillance of JPS, for more information.)
A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function. Recurrent GI bleeding, diarrhea, exudative enteropathy, in addition to associated developmental delay, are associated with a very high rate of morbidity and mortality in these infants, thereby limiting the heritability of such cases.Juvenile polyposis gene(s)
JPS is caused by germline mutations in the SMAD4 gene in approximately 15% to 60% of cases, and to mutations in BMPR1A in approximately 25% to 40% of cases.[481,486,487] The large variability in mutation frequency likely reflects the relatively small number of patients reported in individual studies. A subset of individuals meeting clinical criteria for JPS will not have an identified mutation in either SMAD4 or BMPR1A.
SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer, and germline mutations have been found in 6 of 11 exons. Most mutations are unique, but several recurrent mutations have been identified in multiple independent families.[492,496]
BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with JPS who did not have identifiable mutations in SMAD4. Mutations in BM PR1A include nonsense, frameshift, missense, and splice-site mutations. Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with JPS.[492,496] Rare JPS families have demonstrated mutations in the ENG and PTEN genes, but these have not been confirmed in other studies.[497,498]
JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN.CHEK2
Several studies initially suggested that a subset of families with hereditary breast and colon cancers may have a cancer family syndrome caused by a mutation in the CHEK2 gene.[499-501] However, subsequent studies have suggested that CHEK2 mutations are associated with only a modest increase in CRC risk (i.e., low penetrance). One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (OR, 1.5; 95% CI, 1.2–3.0) of CRC.
Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS-related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS-related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to FCCX. On the basis of available data thus far, clinical testing for CHEK2 mutations is not routinely recommended in clinical practice. There are no established guidelines for CRC screening in individuals with CHEK2 mutations.Hereditary mixed polyposis syndrome (HMPS)
HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas, atypical juvenile polyps and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[504,505] While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder. Linkage analysis of Ashkenazi Jewish families with HMPS revealed shared haplotypes on chromosome 15q13.3. An unusual heterozygous 40kb single-copy duplication was discovered upstream of gremlin 1 (GREM1) that segregated perfectly with individuals and family members with HMPS and not with unaffected controls. The presence of this duplication in HMPS individuals was associated with increased expression of GREM1 transcript levels in the normal intestinal epithelium. GREM1 is a bone morphogenetic protein (BMP) antagonist and thus theoretically would promote the stem cell phenotype in the intestine. Germline mutations leading to defective BMP signaling also underlie JPS, thus drawing a potential link between HMPS and JPS.Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPPS)
Isolated and multiple hyperplastic polyps (HPs) (typically white, flat, and small) are common in the general population, and their presence does not suggest an underlying genetic disorder. Historically, the clinical diagnosis of SPS, as defined by WHO, must satisfy one of the following criteria:
- At least five histologically diagnosed HP occurring proximal to the sigmoid colon (of which at least two are >10 mm in diameter).
- One HP occurring proximal to the sigmoid colon in an individual who has at least one first-degree relative with hyperplastic polyposis.
- More than 30 HPs distributed throughout the colon.
[Note: Other groups have included serrated adenomas as part of the revised clinical criteria for SPS.]
Although the vast majority of cases of SPS lack a family history of HPs, approximately half of the SPS cases have a positive family history of CRC.[509,510] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for SPS is 50% or more.[511-518] One study, using a variation of the WHO criteria for SPS (SPS was defined as at least five histologically diagnosed HPs and/or sessile serrated adenomas (SSAs) proximal to the sigmoid colon, of which two are greater than 10 mm in diameter, or more than 20 HPs and/or SSAs distributed throughout the colon), found a relative risk for CRC in 347 first-degree relatives (41% male) from 57 pedigrees of 5.4 (95% CI, 3.7–7.8).
The WHO criteria are based on expert opinion; and, there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Only two studies to date have found potentially causative germline mutations in SPS individuals.[509,519]
In a study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MYH. One patient was found to have biallelic MYH mutations, and thus was diagnosed with MYH-associated polyposis. No pathogenic mutations were detected in MBD4 among 27 patients tested. However, six patients had SNPs of uncertain significance. Only two patients had a known family history of SPS, and ten of the 38 patients developed CRC. This series presumably included patients with sporadic HPs mixed in with other patients who may have SPS.
In a cohort of 40 SPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline mutation in the EPHB2 gene (D861N). The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline mutations were not found in 100 additional patients with a personal history of CRC or in 200 population-matched healthy control patients.
Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in SPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V600E) was found in polyp tissue. Fifty percent (20 of 40) of HPs from these patients demonstrated the V600E BRAF mutation. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS mutations than left-sided sporadic HPs. In a previous study from this group, HPs from patients with SPS showed a loss of chromosome 1p in 21% (16 of 76) versus 0% in HPs from patients with large HPs (>1 cm), or only five to ten HPs.
Many of the genetic and histological alterations found in HPs of patients with SPS are common with the recently defined CIMP pathway of colorectal adenocarcinoma.Interventions for rare colon cancer syndromes
Individuals with PJS and JPS are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Because of the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[139,521-524] Clinical judgment must be used in making screening recommendations based on published guidelines.Table 14. Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS)
|Organization||STK11 Gene Testing Recommendeda||Age Colon Screening Initiated||Frequency||Method||Extracolonic Screening Recommendations||Comment|
|Johns Hopkins (2006) ||Yes, at age 8 y||18 y||2–3 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes|
|Johns Hopkins (2007) ||Yes, age not specified||Late teens or at onset of symptoms||3 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes||Genetic testing in the late teens or at onset of symptoms.|
|ACPGBI (2007)||18 y||3 y||C or FS + BE||No mention of extracolonic screening||No recommendation for genetic testing; need to consider STK11/LKB1 testing.|
|Cleveland Clinic (2007) ||18 y||3 y||C||Breast, gynecologic (cervix, ovaries), pancreas, small intestine, stomach, testes|
|Erasmus University Medical Center (2010) ||25–30 y||C||Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach|
|NCCN (2014) ||No specific recommendation||Late teens||2–3 y||C||Breast, gynecologic (cervix, ovaries, uterus), lungb, pancreas, small intestine, stomach, testes||Refer to specialized team.|
|ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network.|
|a STK11 mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.|
|bLung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.|
|(Refer to the Other High-Penetrance Syndromes Associated with Breast and/or Ovarian Cancer section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information about PJS and the risk of breast and ovarian cancer.)|
Table 15. Published Recommendations for Diagnosis and Surveillance of Juvenile Polyposis Syndrome (JPS)
|Organization/ Author||SMAD4/BMPR1A Testing Recommendeda||Age Screening Initiated||Frequency||Method||Comment|
|ACPGBI (2007)||15–18 yb||1–2 y||C or FS + BE||Surveillance for gene carriers and affected until age 70 y and discussion of prophylactic surgery.|
|Cleveland Clinic (2007) ||15 y||3 y||C, EGD||Some families with SMAD4 mutation also have HHT; these individuals may need to be screened for HHT.|
|Johns Hopkins (2007) ||Yes, genetic testing preferred over colonoscopy||15 y or at onset of symptoms||Yearly until polyp free then every 2–3 y||C||Prophylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRC.|
|St. Mark's (2012) ||Yes, genetic testing at age 4 y||12 y||1–3 y based on severity||C, EGD||Consider HHT workup.|
|NCCN (2014) ||Yes||~15 y||2–3 y or 1 y if polyps are found||C||Refer to specialized team.|
|ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network.|
|a SMAD4/BMPR1A mutation analysis includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no mutation found by sequencing.|
|bYounger, if patient has presented with symptoms.|
- Bussey HJ: Familial Polyposis Coli: Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment. Baltimore, Md: The Johns Hopkins University Press, 1975.
- Burt RW, Leppert MF, Slattery ML, et al.: Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology 127 (2): 444-51, 2004. [PUBMED Abstract]
- Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996. [PUBMED Abstract]
- Stoffel E, Mukherjee B, Raymond VM, et al.: Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137 (5): 1621-7, 2009. [PUBMED Abstract]
- Aretz S, Uhlhaas S, Goergens H, et al.: MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 119 (4): 807-14, 2006. [PUBMED Abstract]
- Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006. [PUBMED Abstract]
- Coburn MC, Pricolo VE, DeLuca FG, et al.: Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 2 (5): 386-91, 1995. [PUBMED Abstract]
- Desai DC, Neale KF, Talbot IC, et al.: Juvenile polyposis. Br J Surg 82 (1): 14-7, 1995. [PUBMED Abstract]
- Herrera L, ed.: Familial Adenomatous Polyposis. New York, NY: Alan R. Liss Inc, 1990.
- Bülow S: Familial polyposis coli. Dan Med Bull 34 (1): 1-15, 1987. [PUBMED Abstract]
- Campbell WJ, Spence RA, Parks TG: Familial adenomatous polyposis. Br J Surg 81 (12): 1722-33, 1994. [PUBMED Abstract]
- Giardiello FM, Offerhaus JG: Phenotype and cancer risk of various polyposis syndromes. Eur J Cancer 31A (7-8): 1085-7, 1995 Jul-Aug. [PUBMED Abstract]
- Jagelman DG, DeCosse JJ, Bussey HJ: Upper gastrointestinal cancer in familial adenomatous polyposis. Lancet 1 (8595): 1149-51, 1988. [PUBMED Abstract]
- Sturt NJ, Gallagher MC, Bassett P, et al.: Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation. Gut 53 (12): 1832-6, 2004. [PUBMED Abstract]
- Lynch HT, Fitzgibbons R Jr: Surgery, desmoid tumors, and familial adenomatous polyposis: case report and literature review. Am J Gastroenterol 91 (12): 2598-601, 1996. [PUBMED Abstract]
- Bülow S, Björk J, Christensen IJ, et al.: Duodenal adenomatosis in familial adenomatous polyposis. Gut 53 (3): 381-6, 2004. [PUBMED Abstract]
- Burt RW: Colon cancer screening. Gastroenterology 119 (3): 837-53, 2000. [PUBMED Abstract]
- Galiatsatos P, Foulkes WD: Familial adenomatous polyposis. Am J Gastroenterol 101 (2): 385-98, 2006. [PUBMED Abstract]
- Bisgaard ML, Bülow S: Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts. Am J Med Genet A 140 (3): 200-4, 2006. [PUBMED Abstract]
- Berk T, Cohen Z, Bapat B, et al.: Negative genetic test result in familial adenomatous polyposis: clinical screening implications. Dis Colon Rectum 42 (3): 307-10; discussion 310-2, 1999. [PUBMED Abstract]
- Petersen GM, Slack J, Nakamura Y: Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 100 (6): 1658-64, 1991. [PUBMED Abstract]
- Jagelman DG: Clinical management of familial adenomatous polyposis. Cancer Surv 8 (1): 159-67, 1989. [PUBMED Abstract]
- Neale K, Ritchie S, Thomson JP: Screening of offspring of patients with familial adenomatous polyposis: the St. Mark's Hospital polyposis register experience. In: Herrera L, ed.: Familial Adenomatous Polyposis. New York, NY: Alan R. Liss Inc, 1990, pp 61-66.
- Patenaude AF: Cancer susceptibility testing: risks, benefits, and personal beliefs. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 145-156.
- Miyoshi Y, Ando H, Nagase H, et al.: Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A 89 (10): 4452-6, 1992. [PUBMED Abstract]
- Laurent-Puig P, Béroud C, Soussi T: APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 26 (1): 269-70, 1998. [PUBMED Abstract]
- Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75 (5): 951-7, 1993. [PUBMED Abstract]
- Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 43 (4): 548-52, 1998. [PUBMED Abstract]
- Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62 (6): 1290-301, 1998. [PUBMED Abstract]
- Pedemonte S, Sciallero S, Gismondi V, et al.: Novel germline APC variants in patients with multiple adenomas. Genes Chromosomes Cancer 22 (4): 257-67, 1998. [PUBMED Abstract]
- Yan H, Dobbie Z, Gruber SB, et al.: Small changes in expression affect predisposition to tumorigenesis. Nat Genet 30 (1): 25-6, 2002. [PUBMED Abstract]
- Bertario L, Russo A, Sala P, et al.: Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21 (9): 1698-707, 2003. [PUBMED Abstract]
- Rozen P, Samuel Z, Shomrat R, et al.: Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9. Gut 45 (6): 829-33, 1999. [PUBMED Abstract]
- Anthony T, Rodriguez-Bigas MA, Weber TK, et al.: Desmoid tumors. J Am Coll Surg 182 (4): 369-77, 1996. [PUBMED Abstract]
- Eccles DM, van der Luijt R, Breukel C, et al.: Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet 59 (6): 1193-201, 1996. [PUBMED Abstract]
- Bertario L, Russo A, Sala P, et al.: Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 95 (2): 102-7, 2001. [PUBMED Abstract]
- Lynch HT: Desmoid tumors: genotype-phenotype differences in familial adenomatous polyposis--a nosological dilemma. Am J Hum Genet 59 (6): 1184-5, 1996. [PUBMED Abstract]
- Scott RJ, Froggatt NJ, Trembath RC, et al.: Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet 5 (12): 1921-4, 1996. [PUBMED Abstract]
- Caspari R, Olschwang S, Friedl W, et al.: Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet 4 (3): 337-40, 1995. [PUBMED Abstract]
- Davies DR, Armstrong JG, Thakker N, et al.: Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 57 (5): 1151-8, 1995. [PUBMED Abstract]
- Elayi E, Manilich E, Church J: Polishing the crystal ball: knowing genotype improves ability to predict desmoid disease in patients with familial adenomatous polyposis. Dis Colon Rectum 52 (10): 1762-6, 2009. [PUBMED Abstract]
- Nieuwenhuis MH, Lefevre JH, Bülow S, et al.: Family history, surgery, and APC mutation are risk factors for desmoid tumors in familial adenomatous polyposis: an international cohort study. Dis Colon Rectum 54 (10): 1229-34, 2011. [PUBMED Abstract]
- Clark SK, Smith TG, Katz DE, et al.: Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg 85 (7): 970-3, 1998. [PUBMED Abstract]
- Hodgson SV, Maher ER: Gastro-intestinal system. In: Hodgson SV, Maher ER: A Practical Guide to Human Cancer Genetics. 2nd ed. New York, NY: Cambridge University Press, 1999, pp 167-175.
- Rodriguez-Bigas MA, Mahoney MC, Karakousis CP, et al.: Desmoid tumors in patients with familial adenomatous polyposis. Cancer 74 (4): 1270-4, 1994. [PUBMED Abstract]
- Clark SK, Neale KF, Landgrebe JC, et al.: Desmoid tumours complicating familial adenomatous polyposis. Br J Surg 86 (9): 1185-9, 1999. [PUBMED Abstract]
- Belchetz LA, Berk T, Bapat BV, et al.: Changing causes of mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 39 (4): 384-7, 1996. [PUBMED Abstract]
- Iwama T, Tamura K, Morita T, et al.: A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan. Int J Clin Oncol 9 (4): 308-16, 2004. [PUBMED Abstract]
- Church J, Berk T, Boman BM, et al.: Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: a search for a uniform approach to a troubling disease. Dis Colon Rectum 48 (8): 1528-34, 2005. [PUBMED Abstract]
- Parc Y, Piquard A, Dozois RR, et al.: Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy. Ann Surg 239 (3): 378-82, 2004. [PUBMED Abstract]
- Tonelli F, Ficari F, Valanzano R, et al.: Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene. Tumori 89 (4): 391-6, 2003 Jul-Aug. [PUBMED Abstract]
- Hansmann A, Adolph C, Vogel T, et al.: High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 100 (3): 612-20, 2004. [PUBMED Abstract]
- Lindor NM, Dozois R, Nelson H, et al.: Desmoid tumors in familial adenomatous polyposis: a pilot project evaluating efficacy of treatment with pirfenidone. Am J Gastroenterol 98 (8): 1868-74, 2003. [PUBMED Abstract]
- Mace J, Sybil Biermann J, Sondak V, et al.: Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 95 (11): 2373-9, 2002. [PUBMED Abstract]
- Gega M, Yanagi H, Yoshikawa R, et al.: Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 24 (1): 102-5, 2006. [PUBMED Abstract]
- Heiskanen I, Järvinen HJ: Occurrence of desmoid tumours in familial adenomatous polyposis and results of treatment. Int J Colorectal Dis 11 (4): 157-62, 1996. [PUBMED Abstract]
- Latchford AR, Sturt NJ, Neale K, et al.: A 10-year review of surgery for desmoid disease associated with familial adenomatous polyposis. Br J Surg 93 (10): 1258-64, 2006. [PUBMED Abstract]
- Church JM, McGannon E, Hull-Boiner S, et al.: Gastroduodenal polyps in patients with familial adenomatous polyposis. Dis Colon Rectum 35 (12): 1170-3, 1992. [PUBMED Abstract]
- Sarre RG, Frost AG, Jagelman DG, et al.: Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut 28 (3): 306-14, 1987. [PUBMED Abstract]
- Watanabe H, Enjoji M, Yao T, et al.: Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. Hum Pathol 9 (3): 269-83, 1978. [PUBMED Abstract]
- Weston BR, Helper DJ, Rex DK: Positive predictive value of endoscopic features deemed typical of gastric fundic gland polyps. J Clin Gastroenterol 36 (5): 399-402, 2003 May-Jun. [PUBMED Abstract]
- Abraham SC, Nobukawa B, Giardiello FM, et al.: Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol 157 (3): 747-54, 2000. [PUBMED Abstract]
- Odze RD, Marcial MA, Antonioli D: Gastric fundic gland polyps: a morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry. Hum Pathol 27 (9): 896-903, 1996. [PUBMED Abstract]
- Wu TT, Kornacki S, Rashid A, et al.: Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis. Am J Surg Pathol 22 (3): 293-8, 1998. [PUBMED Abstract]
- Burt RW: Gastric fundic gland polyps. Gastroenterology 125 (5): 1462-9, 2003. [PUBMED Abstract]
- Bianchi LK, Burke CA, Bennett AE, et al.: Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 6 (2): 180-5, 2008. [PUBMED Abstract]
- Jalving M, Koornstra JJ, Wesseling J, et al.: Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 24 (9): 1341-8, 2006. [PUBMED Abstract]
- Leggett B: FAP: another indication to treat H pylori. Gut 51 (4): 463-4, 2002. [PUBMED Abstract]
- Nakamura S, Matsumoto T, Kobori Y, et al.: Impact of Helicobacter pylori infection and mucosal atrophy on gastric lesions in patients with familial adenomatous polyposis. Gut 51 (4): 485-9, 2002. [PUBMED Abstract]
- Iida M, Yao T, Itoh H, et al.: Natural history of gastric adenomas in patients with familial adenomatosis coli/Gardner's syndrome. Cancer 61 (3): 605-11, 1988. [PUBMED Abstract]
- Bülow S, Alm T, Fausa O, et al.: Duodenal adenomatosis in familial adenomatous polyposis. DAF Project Group. Int J Colorectal Dis 10 (1): 43-6, 1995. [PUBMED Abstract]
- Park JG, Park KJ, Ahn YO, et al.: Risk of gastric cancer among Korean familial adenomatous polyposis patients. Report of three cases. Dis Colon Rectum 35 (10): 996-8, 1992. [PUBMED Abstract]
- Iwama T, Mishima Y, Utsunomiya J: The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment. Ann Surg 217 (2): 101-8, 1993. [PUBMED Abstract]
- Offerhaus GJ, Giardiello FM, Krush AJ, et al.: The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 102 (6): 1980-2, 1992. [PUBMED Abstract]
- Brosens LA, Keller JJ, Offerhaus GJ, et al.: Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut 54 (7): 1034-43, 2005. [PUBMED Abstract]
- Perzin KH, Bridge MF: Adenomas of the small intestine: a clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer 48 (3): 799-819, 1981. [PUBMED Abstract]
- Ranzi T, Castagnone D, Velio P, et al.: Gastric and duodenal polyps in familial polyposis coli. Gut 22 (5): 363-7, 1981. [PUBMED Abstract]
- Vasen HF, Bülow S, Myrhøj T, et al.: Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis. Gut 40 (6): 716-9, 1997. [PUBMED Abstract]
- Groves CJ, Saunders BP, Spigelman AD, et al.: Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 50 (5): 636-41, 2002. [PUBMED Abstract]
- Burke CA, Santisi J, Church J, et al.: The utility of capsule endoscopy small bowel surveillance in patients with polyposis. Am J Gastroenterol 100 (7): 1498-502, 2005. [PUBMED Abstract]
- Tescher P, Macrae FA, Speer T, et al.: Surveillance of FAP: a prospective blinded comparison of capsule endoscopy and other GI imaging to detect small bowel polyps. Hered Cancer Clin Pract 8 (1): 3, 2010. [PUBMED Abstract]
- Eliakim R: Video capsule endoscopy of the small bowel. Curr Opin Gastroenterol 26 (2): 129-33, 2010. [PUBMED Abstract]
- Taylor SA, Halligan S, Moore L, et al.: Multidetector-row CT duodenography in familial adenomatous polyposis: a pilot study. Clin Radiol 59 (10): 939-45, 2004. [PUBMED Abstract]
- Bleau BL, Gostout CJ: Endoscopic treatment of ampullary adenomas in familial adenomatous polyposis. J Clin Gastroenterol 22 (3): 237-41, 1996. [PUBMED Abstract]
- Norton ID, Gostout CJ: Management of periampullary adenoma. Dig Dis 16 (5): 266-73, 1998 Sep-Oct. [PUBMED Abstract]
- Norton ID, Gostout CJ, Baron TH, et al.: Safety and outcome of endoscopic snare excision of the major duodenal papilla. Gastrointest Endosc 56 (2): 239-43, 2002. [PUBMED Abstract]
- Saurin JC, Gutknecht C, Napoleon B, et al.: Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease. J Clin Oncol 22 (3): 493-8, 2004. [PUBMED Abstract]
- Spigelman AD, Williams CB, Talbot IC, et al.: Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 2 (8666): 783-5, 1989. [PUBMED Abstract]
- Park JS, Choi GS, Kim HJ, et al.: Natural orifice specimen extraction versus conventional laparoscopically assisted right hemicolectomy. Br J Surg 98 (5): 710-5, 2011. [PUBMED Abstract]
- Johnson MD, Mackey R, Brown N, et al.: Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg 14 (2): 229-35, 2010. [PUBMED Abstract]
- de Vos tot Nederveen Cappel WH, Järvinen HJ, Björk J, et al.: Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis. Br J Surg 90 (6): 705-10, 2003. [PUBMED Abstract]
- National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2014. Rockledge, PA: National Comprehensive Cancer Network, 2014. Available online with free registration. Last accessed June 17, 2014.
- Ahmad NA, Kochman ML, Long WB, et al.: Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases. Gastrointest Endosc 55 (3): 390-6, 2002. [PUBMED Abstract]
- Heiskanen I, Kellokumpu I, Järvinen H: Management of duodenal adenomas in 98 patients with familial adenomatous polyposis. Endoscopy 31 (6): 412-6, 1999. [PUBMED Abstract]
- Penna C, Phillips RK, Tiret E, et al.: Surgical polypectomy of duodenal adenomas in familial adenomatous polyposis: experience of two European centres. Br J Surg 80 (8): 1027-9, 1993. [PUBMED Abstract]
- Mackey R, Walsh RM, Chung R, et al.: Pancreas-sparing duodenectomy is effective management for familial adenomatous polyposis. J Gastrointest Surg 9 (8): 1088-93; discussion 1093, 2005. [PUBMED Abstract]
- Lepistö A, Kiviluoto T, Halttunen J, et al.: Surveillance and treatment of duodenal adenomatosis in familial adenomatous polyposis. Endoscopy 41 (6): 504-9, 2009. [PUBMED Abstract]
- Wallace MH, Phillips RK: Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Surg 85 (6): 742-50, 1998. [PUBMED Abstract]
- Parc Y, Mabrut JY, Shields C, et al.: Surgical management of the duodenal manifestations of familial adenomatous polyposis. Br J Surg 98 (4): 480-4, 2011. [PUBMED Abstract]
- Penna C, Bataille N, Balladur P, et al.: Surgical treatment of severe duodenal polyposis in familial adenomatous polyposis. Br J Surg 85 (5): 665-8, 1998. [PUBMED Abstract]
- Hirasawa R, Iishi H, Tatsuta M, et al.: Clinicopathologic features and endoscopic resection of duodenal adenocarcinomas and adenomas with the submucosal saline injection technique. Gastrointest Endosc 46 (6): 507-13, 1997. [PUBMED Abstract]
- Catalano MF, Linder JD, Chak A, et al.: Endoscopic management of adenoma of the major duodenal papilla. Gastrointest Endosc 59 (2): 225-32, 2004. [PUBMED Abstract]
- Alarcon FJ, Burke CA, Church JM, et al.: Familial adenomatous polyposis: efficacy of endoscopic and surgical treatment for advanced duodenal adenomas. Dis Colon Rectum 42 (12): 1533-6, 1999. [PUBMED Abstract]
- Biasco G, Nobili E, Calabrese C, et al.: Impact of surgery on the development of duodenal cancer in patients with familial adenomatous polyposis. Dis Colon Rectum 49 (12): 1860-6, 2006. [PUBMED Abstract]
- Chung RS, Church JM, vanStolk R: Pancreas-sparing duodenectomy: indications, surgical technique, and results. Surgery 117 (3): 254-9, 1995. [PUBMED Abstract]
- Tsiotos GG, Sarr MG: Pancreas-preserving total duodenectomy. Dig Surg 15 (5): 398-403, 1998. [PUBMED Abstract]
- Sarmiento JM, Thompson GB, Nagorney DM, et al.: Pancreas-sparing duodenectomy for duodenal polyposis. Arch Surg 137 (5): 557-62; discussion 562-3, 2002. [PUBMED Abstract]
- Kalady MF, Clary BM, Tyler DS, et al.: Pancreas-preserving duodenectomy in the management of duodenal familial adenomatous polyposis. J Gastrointest Surg 6 (1): 82-7, 2002 Jan-Feb. [PUBMED Abstract]
- Eisenberger CF, Knoefel WT, Peiper M, et al.: Pancreas-sparing duodenectomy in duodenal pathology: indications and results. Hepatogastroenterology 51 (57): 727-31, 2004 May-Jun. [PUBMED Abstract]
- Cetta F, Montalto G, Gori M, et al.: Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J Clin Endocrinol Metab 85 (1): 286-92, 2000. [PUBMED Abstract]
- Cetta F, Curia MC, Montalto G, et al.: Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. J Clin Endocrinol Metab 86 (1): 427-32, 2001. [PUBMED Abstract]
- Jasperson KW, Tuohy TM, Neklason DW, et al.: Hereditary and familial colon cancer. Gastroenterology 138 (6): 2044-58, 2010. [PUBMED Abstract]
- Jarrar AM, Milas M, Mitchell J, et al.: Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 253 (3): 515-21, 2011. [PUBMED Abstract]
- Seki M, Tanaka K, Kikuchi-Yanoshita R, et al.: Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis. Hum Genet 89 (3): 298-300, 1992. [PUBMED Abstract]
- Marchesa P, Fazio VW, Church JM, et al.: Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum 40 (9): 1023-8, 1997. [PUBMED Abstract]
- Cetta F, Mazzarella L, Bon G, et al.: Genetic alterations in hepatoblastoma and hepatocellular carcinoma associated with familial adenomatous polyposis. Med Pediatr Oncol 41 (5): 496-7, 2003. [PUBMED Abstract]
- Young J, Barker M, Robertson T, et al.: A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis. J Clin Pathol 55 (3): 230-1, 2002. [PUBMED Abstract]
- Cetta F, Montalto G, Petracci M: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 41 (3): 417, 1997. [PUBMED Abstract]
- Giardiello FM, Petersen GM, Brensinger JD, et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39 (96): 867-9, 1996. [PUBMED Abstract]
- Ding SF, Michail NE, Habib NA: Genetic changes in hepatoblastoma. J Hepatol 20 (5): 672-5, 1994. [PUBMED Abstract]
- Hughes LJ, Michels VV: Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 43 (6): 1023-5, 1992. [PUBMED Abstract]
- Bernstein IT, Bülow S, Mauritzen K: Hepatoblastoma in two cousins in a family with adenomatous polyposis. Report of two cases. Dis Colon Rectum 35 (4): 373-4, 1992. [PUBMED Abstract]
- Giardiello FM, Offerhaus GJ, Krush AJ, et al.: Risk of hepatoblastoma in familial adenomatous polyposis. J Pediatr 119 (5): 766-8, 1991. [PUBMED Abstract]
- Perilongo G: Link confirmed between FAP and hepatoblastoma. Oncology (Huntingt) 5 (7): 14, 1991. [PUBMED Abstract]
- Toyama WM, Wagner S: Hepatoblastoma with familial polyposis coli: another case and corrected pedigree. Surgery 108 (1): 123-4, 1990. [PUBMED Abstract]
- Kurahashi H, Takami K, Oue T, et al.: Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res 55 (21): 5007-11, 1995. [PUBMED Abstract]
- Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005. [PUBMED Abstract]
- Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47 (6): 811-8, 2006. [PUBMED Abstract]
- Hamilton SR, Liu B, Parsons RE, et al.: The molecular basis of Turcot's syndrome. N Engl J Med 332 (13): 839-47, 1995. [PUBMED Abstract]
- Petersen GM, Francomano C, Kinzler K, et al.: Presymptomatic direct detection of adenomatous polyposis coli (APC) gene mutations in familial adenomatous polyposis. Hum Genet 91 (4): 307-11, 1993. [PUBMED Abstract]
- Fearnhead NS, Britton MP, Bodmer WF: The ABC of APC. Hum Mol Genet 10 (7): 721-33, 2001. [PUBMED Abstract]
- Sieber OM, Lamlum H, Crabtree MD, et al.: Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. Proc Natl Acad Sci U S A 99 (5): 2954-8, 2002. [PUBMED Abstract]
- Michils G, Tejpar S, Thoelen R, et al.: Large deletions of the APC gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study. Hum Mutat 25 (2): 125-34, 2005. [PUBMED Abstract]
- Meuller J, Kanter-Smoler G, Nygren AO, et al.: Identification of genomic deletions of the APC gene in familial adenomatous polyposis by two independent quantitative techniques. Genet Test 8 (3): 248-56, 2004. [PUBMED Abstract]
- Sieber OM, Lipton L, Crabtree M, et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348 (9): 791-9, 2003. [PUBMED Abstract]
- Fearnhead NS: Familial adenomatous polyposis and MYH. Lancet 362 (9377): 5-6, 2003. [PUBMED Abstract]
- Al-Tassan N, Chmiel NH, Maynard J, et al.: Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet 30 (2): 227-32, 2002. [PUBMED Abstract]
- Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003. [PUBMED Abstract]
- Dunlop MG; British Society for GastroenterologyAssociation of Coloproctology for Great Britain and Ireland: Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 51 (Suppl 5): V21-7, 2002. [PUBMED Abstract]
- Church J, Simmang C; Standards Task Force, et al.: Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum 46 (8): 1001-12, 2003. [PUBMED Abstract]
- Church J, Lowry A, Simmang C, et al.: Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. Dis Colon Rectum 44 (10): 1404-12, 2001. [PUBMED Abstract]
- Standard Task Force, American Society of Colon and Rectal Surgeons, Collaborative Group of the Americas on Inherited Colorectal Cancer: Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer. Dis Colon Rectum 44 (10): 1403, 2001. [PUBMED Abstract]
- Smith RA, Cokkinides V, von Eschenbach AC, et al.: American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 52 (1): 8-22, 2002 Jan-Feb. [PUBMED Abstract]
- Petersen GM: Genetic testing and counseling in familial adenomatous polyposis. Oncology (Huntingt) 10 (1): 89-94; discussion 97-8, 1996. [PUBMED Abstract]
- Church J, Burke C, McGannon E, et al.: Risk of rectal cancer in patients after colectomy and ileorectal anastomosis for familial adenomatous polyposis: a function of available surgical options. Dis Colon Rectum 46 (9): 1175-81, 2003. [PUBMED Abstract]
- Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Ann Surg Oncol 13 (10): 1296-321, 2006. [PUBMED Abstract]
- Bertario L, Russo A, Radice P, et al.: Genotype and phenotype factors as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Hereditary Colorectal Tumors Registry. Ann Surg 231 (4): 538-43, 2000. [PUBMED Abstract]
- Heiskanen I, Järvinen HJ: Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Int J Colorectal Dis 12 (1): 9-13, 1997. [PUBMED Abstract]
- Bassuini MM, Billings PJ: Carcinoma in an ileoanal pouch after restorative proctocolectomy for familial adenomatous polyposis. Br J Surg 83 (4): 506, 1996. [PUBMED Abstract]
- Vrouenraets BC, Van Duijvendijk P, Bemelman WA, et al.: Adenocarcinoma in the anal canal after ileal pouch-anal anastomosis for familial adenomatous polyposis using a double-stapled technique: report of two cases. Dis Colon Rectum 47 (4): 530-4, 2004. [PUBMED Abstract]
- De Cosse JJ, Bülow S, Neale K, et al.: Rectal cancer risk in patients treated for familial adenomatous polyposis. The Leeds Castle Polyposis Group. Br J Surg 79 (12): 1372-5, 1992. [PUBMED Abstract]
- Nugent KP, Phillips RK: Rectal cancer risk in older patients with familial adenomatous polyposis and an ileorectal anastomosis: a cause for concern. Br J Surg 79 (11): 1204-6, 1992. [PUBMED Abstract]
- Bess MA, Adson MA, Elveback LR, et al.: Rectal cancer following colectomy for polyposis. Arch Surg 115 (4): 460-7, 1980. [PUBMED Abstract]
- Iwama T, Mishima Y: Factors affecting the risk of rectal cancer following rectum-preserving surgery in patients with familial adenomatous polyposis. Dis Colon Rectum 37 (10): 1024-6, 1994. [PUBMED Abstract]
- Setti-Carraro P, Nicholls RJ: Choice of prophylactic surgery for the large bowel component of familial adenomatous polyposis. Br J Surg 83 (7): 885-92, 1996. [PUBMED Abstract]
- Vasen HF, van der Luijt RB, Slors JF, et al.: Molecular genetic tests as a guide to surgical management of familial adenomatous polyposis. Lancet 348 (9025): 433-5, 1996. [PUBMED Abstract]
- Wu JS, Paul P, McGannon EA, et al.: APC genotype, polyp number, and surgical options in familial adenomatous polyposis. Ann Surg 227 (1): 57-62, 1998. [PUBMED Abstract]
- Bülow S, Højen H, Buntzen S, et al.: Primary and secondary restorative proctocolectomy for familial adenomatous polyposis: complications and long-term bowel function. Colorectal Dis 15 (4): 436-41, 2013. [PUBMED Abstract]
- Church J, Burke C, McGannon E, et al.: Predicting polyposis severity by proctoscopy: how reliable is it? Dis Colon Rectum 44 (9): 1249-54, 2001. [PUBMED Abstract]
- Nieuwenhuis MH, Bülow S, Björk J, et al.: Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery. Dis Colon Rectum 52 (7): 1259-63, 2009. [PUBMED Abstract]
- Nieuwenhuis MH, Mathus-Vliegen LM, Slors FJ, et al.: Genotype-phenotype correlations as a guide in the management of familial adenomatous polyposis. Clin Gastroenterol Hepatol 5 (3): 374-8, 2007. [PUBMED Abstract]
- Parc YR, Olschwang S, Desaint B, et al.: Familial adenomatous polyposis: prevalence of adenomas in the ileal pouch after restorative proctocolectomy. Ann Surg 233 (3): 360-4, 2001. [PUBMED Abstract]
- Groves CJ, Beveridge G, Swain DJ, et al.: Prevalence and morphology of pouch and ileal adenomas in familial adenomatous polyposis. Dis Colon Rectum 48 (4): 816-23, 2005. [PUBMED Abstract]
- Ooi BS, Remzi FH, Gramlich T, et al.: Anal transitional zone cancer after restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis: report of two cases. Dis Colon Rectum 46 (10): 1418-23; discussion 1422-3, 2003. [PUBMED Abstract]
- Lovegrove RE, Tilney HS, Heriot AG, et al.: A comparison of adverse events and functional outcomes after restorative proctocolectomy for familial adenomatous polyposis and ulcerative colitis. Dis Colon Rectum 49 (9): 1293-306, 2006. [PUBMED Abstract]
- Steinbach G, Lynch PM, Phillips RK, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342 (26): 1946-52, 2000. [PUBMED Abstract]
- Giardiello FM, Yang VW, Hylind LM, et al.: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 346 (14): 1054-9, 2002. [PUBMED Abstract]
- Lynch PM, Ayers GD, Hawk E, et al.: The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 105 (6): 1437-43, 2010. [PUBMED Abstract]
- West NJ, Clark SK, Phillips RK, et al.: Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 59 (7): 918-25, 2010. [PUBMED Abstract]
- Phillips RK, Wallace MH, Lynch PM, et al.: A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50 (6): 857-60, 2002. [PUBMED Abstract]
- Nugent KP, Farmer KC, Spigelman AD, et al.: Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80 (12): 1618-9, 1993. [PUBMED Abstract]
- Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med 351 (17): 1709-11, 2004. [PUBMED Abstract]
- NIH Halts Use of COX-2 Inhibitor in Large Cancer Prevention Trial. Bethesda, Md: National Cancer Institute, 2004. Available online. Last accessed October 16, 2013.
- Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11): 1071-80, 2005. [PUBMED Abstract]
- Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (11): 1092-102, 2005. [PUBMED Abstract]
- Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328 (18): 1313-6, 1993. [PUBMED Abstract]
- Leppert M, Burt R, Hughes JP, et al.: Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322 (13): 904-8, 1990. [PUBMED Abstract]
- Giardiello FM, Brensinger JD, Luce MC, et al.: Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene. Ann Intern Med 126 (7): 514-9, 1997. [PUBMED Abstract]
- White S, Bubb VJ, Wyllie AH: Germline APC mutation (Gln1317) in a cancer-prone family that does not result in familial adenomatous polyposis. Genes Chromosomes Cancer 15 (2): 122-8, 1996. [PUBMED Abstract]
- Gonçalves V, Theisen P, Antunes O, et al.: A missense mutation in the APC tumor suppressor gene disrupts an ASF/SF2 splicing enhancer motif and causes pathogenic skipping of exon 14. Mutat Res 662 (1-2): 33-6, 2009. [PUBMED Abstract]
- Lynch HT, Smyrk TC: Classification of familial adenomatous polyposis: a diagnostic nightmare. Am J Hum Genet 62 (6): 1288-9, 1998. [PUBMED Abstract]
- Knudsen AL, Bisgaard ML, Bülow S: Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2 (1): 43-55, 2003. [PUBMED Abstract]
- Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61 (2): 153-61, 2007. [PUBMED Abstract]
- Scott RJ, Meldrum C, Crooks R, et al.: Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity. Gut 48 (4): 508-14, 2001. [PUBMED Abstract]
- Vasen HF, Möslein G, Alonso A, et al.: Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57 (5): 704-13, 2008. [PUBMED Abstract]
- Hampel H: Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 18 (4): 687-703, 2009. [PUBMED Abstract]
- Jones N, Vogt S, Nielsen M, et al.: Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137 (2): 489-94, 494.e1; quiz 725-6, 2009. [PUBMED Abstract]
- Nieuwenhuis MH, Vogt S, Jones N, et al.: Evidence for accelerated colorectal adenoma--carcinoma progression in MUTYH-associated polyposis? Gut 61 (5): 734-8, 2012. [PUBMED Abstract]
- Grover S, Kastrinos F, Steyerberg EW, et al.: Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA 308 (5): 485-92, 2012. [PUBMED Abstract]
- Sampson JR, Dolwani S, Jones S, et al.: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362 (9377): 39-41, 2003. [PUBMED Abstract]
- Morak M, Laner A, Bacher U, et al.: MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 78 (4): 353-63, 2010. [PUBMED Abstract]
- Nielsen M, Morreau H, Vasen HF, et al.: MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 79 (1): 1-16, 2011. [PUBMED Abstract]
- Nascimbeni R, Pucciarelli S, Di Lorenzo D, et al.: Rectum-sparing surgery may be appropriate for biallelic MutYH-associated polyposis. Dis Colon Rectum 53 (12): 1670-5, 2010. [PUBMED Abstract]
- Win AK, Cleary SP, Dowty JG, et al.: Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer 129 (9): 2256-62, 2011. [PUBMED Abstract]
- Vogt S, Jones N, Christian D, et al.: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137 (6): 1976-85.e1-10, 2009. [PUBMED Abstract]
- Gismondi V, Meta M, Bonelli L, et al.: Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 109 (5): 680-4, 2004. [PUBMED Abstract]
- Lefevre JH, Rodrigue CM, Mourra N, et al.: Implication of MYH in colorectal polyposis. Ann Surg 244 (6): 874-9; discussion 879-80, 2006. [PUBMED Abstract]
- Wasielewski M, Out AA, Vermeulen J, et al.: Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. Breast Cancer Res Treat 124 (3): 635-41, 2010. [PUBMED Abstract]
- Poulsen ML, Bisgaard ML: MUTYH Associated Polyposis (MAP). Curr Genomics 9 (6): 420-35, 2008. [PUBMED Abstract]
- Goodenberger M, Lindor NM: Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol 45 (6): 488-500, 2011. [PUBMED Abstract]
- Win AK, Hopper JL, Jenkins MA: Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam Cancer 10 (1): 1-9, 2011. [PUBMED Abstract]
- Giráldez MD, Balaguer F, Caldés T, et al.: Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 8 (4): 525-31, 2009. [PUBMED Abstract]
- Nielsen M, Joerink-van de Beld MC, Jones N, et al.: Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology 136 (2): 471-6, 2009. [PUBMED Abstract]
- Balaguer F, Castellví-Bel S, Castells A, et al.: Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol 5 (3): 379-87, 2007. [PUBMED Abstract]
- Beggs AD, Domingo E, Abulafi M, et al.: A study of genomic instability in early preneoplastic colonic lesions. Oncogene 32 (46): 5333-7, 2013. [PUBMED Abstract]
- Yurgelun MB, Goel A, Hornick JL, et al.: Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 5 (4): 574-82, 2012. [PUBMED Abstract]
- Spirio L, Otterud B, Stauffer D, et al.: Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 51 (1): 92-100, 1992. [PUBMED Abstract]
- Wang L, Baudhuin LM, Boardman LA, et al.: MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 127 (1): 9-16, 2004. [PUBMED Abstract]
- Palles C, Cazier JB, Howarth KM, et al.: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45 (2): 136-44, 2013. [PUBMED Abstract]
- Briggs S, Tomlinson I: Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol 230 (2): 148-53, 2013. [PUBMED Abstract]
- Hazewinkel Y, López-Cerón M, East JE, et al.: Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging. Gastrointest Endosc 77 (6): 916-24, 2013. [PUBMED Abstract]
- Guarinos C, Juárez M, Egoavil C, et al.: Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. Clin Cancer Res 20 (5): 1158-68, 2014. [PUBMED Abstract]
- Crockett SD, Snover DC, Ahnen DJ, et al.: Sessile Serrated Adenomas: An Evidence-Based Guide to Management. Clin Gastroenterol Hepatol : , 2013. [PUBMED Abstract]
- Boparai KS, Mathus-Vliegen EM, Koornstra JJ, et al.: Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study. Gut 59 (8): 1094-100, 2010. [PUBMED Abstract]
- Clendenning M, Young JP, Walsh MD, et al.: Germline Mutations in the Polyposis-Associated Genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1 Are Not Common in Individuals with Serrated Polyposis Syndrome. PLoS One 8 (6): e66705, 2013. [PUBMED Abstract]
- Boland CR: Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4 (3): 211-8, 2005. [PUBMED Abstract]
- Lindor NM, Rabe K, Petersen GM, et al.: Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293 (16): 1979-85, 2005. [PUBMED Abstract]
- Boland CR: Hereditary nonpolyposis colorectal cancer. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. New York, NY: McGraw-Hill, 1998, pp 333-346.
- Lynch HT, Lanspa S, Smyrk T, et al.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, Part I. Cancer Genet Cytogenet 53 (2): 143-60, 1991. [PUBMED Abstract]
- Lynch HT, Smyrk TC, Watson P, et al.: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104 (5): 1535-49, 1993. [PUBMED Abstract]
- Hampel H, Frankel WL, Martin E, et al.: Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26 (35): 5783-8, 2008. [PUBMED Abstract]
- Hampel H, Frankel WL, Martin E, et al.: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352 (18): 1851-60, 2005. [PUBMED Abstract]
- Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4 (3): 219-25, 2005. [PUBMED Abstract]
- Jemal A, Siegel R, Xu J, et al.: Cancer statistics, 2010. CA Cancer J Clin 60 (5): 277-300, 2010 Sep-Oct. [PUBMED Abstract]
- Hampel H, Stephens JA, Pukkala E, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129 (2): 415-21, 2005. [PUBMED Abstract]
- Chen S, Wang W, Lee S, et al.: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296 (12): 1479-87, 2006. [PUBMED Abstract]
- Quehenberger F, Vasen HF, van Houwelingen HC: Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 42 (6): 491-6, 2005. [PUBMED Abstract]
- Baglietto L, Lindor NM, Dowty JG, et al.: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 102 (3): 193-201, 2010. [PUBMED Abstract]
- Senter L, Clendenning M, Sotamaa K, et al.: The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135 (2): 419-28, 2008. [PUBMED Abstract]
- Bonadona V, Bonaïti B, Olschwang S, et al.: Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305 (22): 2304-10, 2011. [PUBMED Abstract]
- Win AK, Young JP, Lindor NM, et al.: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30 (9): 958-64, 2012. [PUBMED Abstract]
- De Jong AE, Morreau H, Van Puijenbroek M, et al.: The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology 126 (1): 42-8, 2004. [PUBMED Abstract]
- Lu KH, Dinh M, Kohlmann W, et al.: Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 105 (3): 569-74, 2005. [PUBMED Abstract]
- Tan YY, McGaughran J, Ferguson K, et al.: Improving identification of lynch syndrome patients: a comparison of research data with clinical records. Int J Cancer 132 (12): 2876-83, 2013. [PUBMED Abstract]
- Kempers MJ, Kuiper RP, Ockeloen CW, et al.: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 12 (1): 49-55, 2011. [PUBMED Abstract]
- Win AK, Lindor NM, Winship I, et al.: Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 105 (4): 274-9, 2013. [PUBMED Abstract]
- Broaddus RR, Lynch HT, Chen LM, et al.: Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer 106 (1): 87-94, 2006. [PUBMED Abstract]
- Garg K, Leitao MM Jr, Kauff ND, et al.: Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol 33 (6): 925-33, 2009. [PUBMED Abstract]
- Vasen HF, Offerhaus GJ, den Hartog Jager FC, et al.: The tumour spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int J Cancer 46 (1): 31-4, 1990. [PUBMED Abstract]
- Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993. [PUBMED Abstract]
- Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]
- Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995. [PUBMED Abstract]
- Ketabi Z, Bartuma K, Bernstein I, et al.: Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol 121 (3): 462-5, 2011. [PUBMED Abstract]
- Raymond VM, Everett JN, Furtado LV, et al.: Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 31 (24): 3012-8, 2013. [PUBMED Abstract]
- Raymond VM, Mukherjee B, Wang F, et al.: Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 31 (14): 1713-8, 2013. [PUBMED Abstract]
- Jensen UB, Sunde L, Timshel S, et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120 (3): 777-82, 2010. [PUBMED Abstract]
- Shanley S, Fung C, Milliken J, et al.: Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer 8 (3): 251-5, 2009. [PUBMED Abstract]
- Walsh MD, Buchanan DD, Cummings MC, et al.: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res 16 (7): 2214-24, 2010. [PUBMED Abstract]
- Buerki N, Gautier L, Kovac M, et al.: Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer 51 (1): 83-91, 2012. [PUBMED Abstract]
- Win AK, Lindor NM, Young JP, et al.: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 104 (18): 1363-72, 2012. [PUBMED Abstract]
- Bapat B, Xia L, Madlensky L, et al.: The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet 59 (3): 736-9, 1996. [PUBMED Abstract]
- Lynch HT, Lynch PM, Pester J, et al.: The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med 141 (5): 607-11, 1981. [PUBMED Abstract]
- Suspiro A, Fidalgo P, Cravo M, et al.: The Muir-Torre syndrome: a rare variant of hereditary nonpolyposis colorectal cancer associated with hMSH2 mutation. Am J Gastroenterol 93 (9): 1572-4, 1998. [PUBMED Abstract]
- Kruse R, Rütten A, Lamberti C, et al.: Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet 63 (1): 63-70, 1998. [PUBMED Abstract]
- South CD, Hampel H, Comeras I, et al.: The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst 100 (4): 277-81, 2008. [PUBMED Abstract]
- Kastrinos F, Stoffel EM, Balmaña J, et al.: Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev 17 (8): 2044-51, 2008. [PUBMED Abstract]
- Vasen HF, Mecklin JP, Khan PM, et al.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34 (5): 424-5, 1991. [PUBMED Abstract]
- Vasen HF, Watson P, Mecklin JP, et al.: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116 (6): 1453-6, 1999. [PUBMED Abstract]
- Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89 (23): 1758-62, 1997. [PUBMED Abstract]
- Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96 (4): 261-8, 2004. [PUBMED Abstract]
- Laghi L, Bianchi P, Roncalli M, et al.: Re: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96 (18): 1402-3; author reply 1403-4, 2004. [PUBMED Abstract]
- Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997. [PUBMED Abstract]
- Akiyama Y, Sato H, Yamada T, et al.: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57 (18): 3920-3, 1997. [PUBMED Abstract]
- Wu Y, Berends MJ, Mensink RG, et al.: Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 65 (5): 1291-8, 1999. [PUBMED Abstract]
- Kolodner RD, Tytell JD, Schmeits JL, et al.: Germ-line msh6 mutations in colorectal cancer families. Cancer Res 59 (20): 5068-74, 1999. [PUBMED Abstract]
- Plaschke J, Engel C, Krüger S, et al.: Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 22 (22): 4486-94, 2004. [PUBMED Abstract]
- Wijnen JT, Vasen HF, Khan PM, et al.: Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339 (8): 511-8, 1998. [PUBMED Abstract]
- Syngal S, Fox EA, Li C, et al.: Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 282 (3): 247-53, 1999. [PUBMED Abstract]
- Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006. [PUBMED Abstract]
- Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006. [PUBMED Abstract]
- Kastrinos F, Allen JI, Stockwell DH, et al.: Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol 104 (6): 1508-18, 2009. [PUBMED Abstract]
- Khan O, Blanco A, Conrad P, et al.: Performance of Lynch syndrome predictive models in a multi-center US referral population. Am J Gastroenterol 106 (10): 1822-7; quiz 1828, 2011. [PUBMED Abstract]
- Jasperson KW, Vu TM, Schwab AL, et al.: Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis. Fam Cancer 9 (2): 99-107, 2010. [PUBMED Abstract]
- Müller A, Beckmann C, Westphal G, et al.: Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study. Int J Colorectal Dis 21 (7): 632-41, 2006. [PUBMED Abstract]
- Weber JL, May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44 (3): 388-96, 1989. [PUBMED Abstract]
- Vilar E, Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7 (3): 153-62, 2010. [PUBMED Abstract]
- Aaltonen LA, Peltomäki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 260 (5109): 812-6, 1993. [PUBMED Abstract]
- Jenkins MA, Hayashi S, O'Shea AM, et al.: Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 133 (1): 48-56, 2007. [PUBMED Abstract]
- Greenson JK, Bonner JD, Ben-Yzhak O, et al.: Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 27 (5): 563-70, 2003. [PUBMED Abstract]
- Boland CR, Thibodeau SN, Hamilton SR, et al.: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58 (22): 5248-57, 1998. [PUBMED Abstract]
- Hendriks YM, Wagner A, Morreau H, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 127 (1): 17-25, 2004. [PUBMED Abstract]
- Parc YR, Halling KC, Wang L, et al.: HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60 (8): 2225-31, 2000. [PUBMED Abstract]
- Cunningham JM, Kim CY, Christensen ER, et al.: The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69 (4): 780-90, 2001. [PUBMED Abstract]
- Yuen ST, Chan TL, Ho JW, et al.: Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 21 (49): 7585-92, 2002. [PUBMED Abstract]
- Raedle J, Trojan J, Brieger A, et al.: Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med 135 (8 Pt 1): 566-76, 2001. [PUBMED Abstract]
- Bouzourene H, Hutter P, Losi L, et al.: Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer 9 (2): 167-72, 2010. [PUBMED Abstract]
- Payá A, Alenda C, Pérez-Carbonell L, et al.: Utility of p16 immunohistochemistry for the identification of Lynch syndrome. Clin Cancer Res 15 (9): 3156-62, 2009. [PUBMED Abstract]
- Wang L, Cunningham JM, Winters JL, et al.: BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63 (17): 5209-12, 2003. [PUBMED Abstract]
- Domingo E, Espín E, Armengol M, et al.: Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer 39 (2): 138-42, 2004. [PUBMED Abstract]
- Deng G, Bell I, Crawley S, et al.: BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10 (1 Pt 1): 191-5, 2004. [PUBMED Abstract]
- Domingo E, Niessen RC, Oliveira C, et al.: BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 24 (24): 3995-8, 2005. [PUBMED Abstract]
- Hitchins MP, Ward RL: Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet 46 (12): 793-802, 2009. [PUBMED Abstract]
- Chan AT, Zauber AG, Hsu M, et al.: Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma. Gastroenterology 136 (7): 2127-2136.e1, 2009. [PUBMED Abstract]
- Ligtenberg MJ, Kuiper RP, Chan TL, et al.: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet 41 (1): 112-7, 2009. [PUBMED Abstract]
- Kovacs ME, Papp J, Szentirmay Z, et al.: Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30 (2): 197-203, 2009. [PUBMED Abstract]
- Lynch HT, Riegert-Johnson DL, Snyder C, et al.: Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol 106 (10): 1829-36, 2011. [PUBMED Abstract]
- Thibodeau SN, French AJ, Roche PC, et al.: Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56 (21): 4836-40, 1996. [PUBMED Abstract]
- Cawkwell L, Gray S, Murgatroyd H, et al.: Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut 45 (3): 409-15, 1999. [PUBMED Abstract]
- Lindor NM, Burgart LJ, Leontovich O, et al.: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20 (4): 1043-8, 2002. [PUBMED Abstract]
- de La Chapelle A: Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 20 (4): 897-9, 2002. [PUBMED Abstract]
- Piñol V, Castells A, Andreu M, et al.: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293 (16): 1986-94, 2005. [PUBMED Abstract]
- Baudhuin LM, Burgart LJ, Leontovich O, et al.: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer 4 (3): 255-65, 2005. [PUBMED Abstract]
- Lagerstedt Robinson K, Liu T, Vandrovcova J, et al.: Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 99 (4): 291-9, 2007. [PUBMED Abstract]
- Schofield L, Watson N, Grieu F, et al.: Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer 124 (5): 1097-102, 2009. [PUBMED Abstract]
- Engel C, Forberg J, Holinski-Feder E, et al.: Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer 118 (1): 115-22, 2006. [PUBMED Abstract]
- Hall G, Clarkson A, Shi A, et al.: Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology 42 (5): 409-13, 2010. [PUBMED Abstract]
- Perez-Cabornero L, Velasco E, Infante M, et al.: A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR. Eur J Cancer 45 (8): 1485-93, 2009. [PUBMED Abstract]
- Charbonnier F, Olschwang S, Wang Q, et al.: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 62 (3): 848-53, 2002. [PUBMED Abstract]
- Wagner A, Barrows A, Wijnen JT, et al.: Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72 (5): 1088-100, 2003. [PUBMED Abstract]
- Wang Y, Friedl W, Lamberti C, et al.: Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer 103 (5): 636-41, 2003. [PUBMED Abstract]
- Baudhuin LM, Ferber MJ, Winters JL, et al.: Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 129 (3): 846-54, 2005. [PUBMED Abstract]
- Grabowski M, Mueller-Koch Y, Grasbon-Frodl E, et al.: Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet Test 9 (2): 138-46, 2005. [PUBMED Abstract]
- Mangold E, Pagenstecher C, Friedl W, et al.: Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer 116 (5): 692-702, 2005. [PUBMED Abstract]
- Peltomäki P, Aaltonen LA, Sistonen P, et al.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260 (5109): 810-2, 1993. [PUBMED Abstract]
- Lindblom A, Tannergård P, Werelius B, et al.: Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet 5 (3): 279-82, 1993. [PUBMED Abstract]
- Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368 (6468): 258-61, 1994. [PUBMED Abstract]
- Fishel R, Lescoe MK, Rao MR, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75 (5): 1027-38, 1993. [PUBMED Abstract]
- Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75 (6): 1215-25, 1993. [PUBMED Abstract]
- Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994. [PUBMED Abstract]
- Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994. [PUBMED Abstract]
- Worthley DL, Walsh MD, Barker M, et al.: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128 (5): 1431-6, 2005. [PUBMED Abstract]
- Marra G, Boland CR: Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87 (15): 1114-25, 1995. [PUBMED Abstract]
- Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997. [PUBMED Abstract]
- Mitchell RJ, Farrington SM, Dunlop MG, et al.: Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Am J Epidemiol 156 (10): 885-902, 2002. [PUBMED Abstract]
- Foulkes WD, Thiffault I, Gruber SB, et al.: The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am J Hum Genet 71 (6): 1395-412, 2002. [PUBMED Abstract]
- Pinheiro M, Pinto C, Peixoto A, et al.: A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. Genet Med 13 (10): 895-902, 2011. [PUBMED Abstract]
- Tomsic J, Liyanarachchi S, Hampel H, et al.: An American founder mutation in MLH1. Int J Cancer 130 (9): 2088-95, 2012. [PUBMED Abstract]
- Ainsworth PJ, Koscinski D, Fraser BP, et al.: Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1. Clin Genet 66 (3): 183-8, 2004. [PUBMED Abstract]
- Gruber SB: New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 130 (2): 577-87, 2006. [PUBMED Abstract]
- Peltomäki P: Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21 (6): 1174-9, 2003. [PUBMED Abstract]
- Choi YH, Cotterchio M, McKeown-Eyssen G, et al.: Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Pract 7 (1): 14, 2009. [PUBMED Abstract]
- Lin KM, Shashidharan M, Thorson AG, et al.: Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J Gastrointest Surg 2 (1): 67-71, 1998 Jan-Feb. [PUBMED Abstract]
- Scott RJ, McPhillips M, Meldrum CJ, et al.: Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68 (1): 118-127, 2001. [PUBMED Abstract]
- Wijnen J, de Leeuw W, Vasen H, et al.: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23 (2): 142-4, 1999. [PUBMED Abstract]
- Goodfellow PJ, Buttin BM, Herzog TJ, et al.: Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A 100 (10): 5908-13, 2003. [PUBMED Abstract]
- de Leeuw WJ, Dierssen J, Vasen HF, et al.: Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol 192 (3): 328-35, 2000. [PUBMED Abstract]
- Rumilla K, Schowalter KV, Lindor NM, et al.: Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn 13 (1): 93-9, 2011. [PUBMED Abstract]
- Berends MJ, Wu Y, Sijmons RH, et al.: Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet 70 (1): 26-37, 2002. [PUBMED Abstract]
- Ramsoekh D, Wagner A, van Leerdam ME, et al.: A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut 57 (11): 1539-44, 2008. [PUBMED Abstract]
- Peltomäki P, Vasen H: Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20 (4-5): 269-76, 2004. [PUBMED Abstract]
- Peterlongo P, Nafa K, Lerman GS, et al.: MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 107 (4): 571-9, 2003. [PUBMED Abstract]
- Schweizer P, Moisio AL, Kuismanen SA, et al.: Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer. Cancer Res 61 (7): 2813-5, 2001. [PUBMED Abstract]
- Truninger K, Menigatti M, Luz J, et al.: Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128 (5): 1160-71, 2005. [PUBMED Abstract]
- Baudhuin LM, Mai M, French AJ, et al.: Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods. J Mol Diagn 7 (2): 226-35, 2005. [PUBMED Abstract]
- Nakagawa H, Lockman JC, Frankel WL, et al.: Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64 (14): 4721-7, 2004. [PUBMED Abstract]
- Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130 (2): 312-22, 2006. [PUBMED Abstract]
- Reeves SG, Rich D, Meldrum CJ, et al.: IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. Int J Cancer 123 (6): 1339-43, 2008. [PUBMED Abstract]
- Zecevic M, Amos CI, Gu X, et al.: IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst 98 (2): 139-43, 2006. [PUBMED Abstract]
- Kong S, Amos CI, Luthra R, et al.: Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res 60 (2): 249-52, 2000. [PUBMED Abstract]
- Talseth BA, Ashton KA, Meldrum C, et al.: Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer 122 (6): 1273-7, 2008. [PUBMED Abstract]
- Bala S, Peltomäki P: CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res 61 (16): 6042-5, 2001. [PUBMED Abstract]
- Wijnen JT, Brohet RM, van Eijk R, et al.: Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology 136 (1): 131-7, 2009. [PUBMED Abstract]
- Talseth-Palmer BA, Brenne IS, Ashton KA, et al.: Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in Lynch syndrome. J Med Genet 48 (4): 279-84, 2011. [PUBMED Abstract]
- Houlle S, Charbonnier F, Houivet E, et al.: Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers. Eur J Hum Genet 19 (8): 887-92, 2011. [PUBMED Abstract]
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group: Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11 (1): 35-41, 2009. [PUBMED Abstract]
- Palomaki GE, McClain MR, Melillo S, et al.: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 11 (1): 42-65, 2009. [PUBMED Abstract]
- Ladabaum U, Wang G, Terdiman J, et al.: Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 155 (2): 69-79, 2011. [PUBMED Abstract]
- Dinh TA, Rosner BI, Atwood JC, et al.: Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila) 4 (1): 9-22, 2011. [PUBMED Abstract]
- Bellcross CA, Bedrosian SR, Daniels E, et al.: Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting. Genet Med 14 (1): 152-62, 2012. [PUBMED Abstract]
- Cohen SA: Current Lynch syndrome tumor screening practices: a survey of genetic counselors. J Genet Couns 23 (1): 38-47, 2014. [PUBMED Abstract]
- Beamer LC, Grant ML, Espenschied CR, et al.: Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 30 (10): 1058-63, 2012. [PUBMED Abstract]
- Moreira L, Balaguer F, Lindor N, et al.: Identification of Lynch syndrome among patients with colorectal cancer. JAMA 308 (15): 1555-65, 2012. [PUBMED Abstract]
- Ward RL, Hicks S, Hawkins NJ: Population-based molecular screening for Lynch syndrome: implications for personalized medicine. J Clin Oncol 31 (20): 2554-62, 2013. [PUBMED Abstract]
- Heald B, Plesec T, Liu X, et al.: Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol 31 (10): 1336-40, 2013. [PUBMED Abstract]
- Chubak B, Heald B, Sharp RR: Informed consent to microsatellite instability and immunohistochemistry screening for Lynch syndrome. Genet Med 13 (4): 356-60, 2011. [PUBMED Abstract]
- Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
- Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
- Kwon JS, Scott JL, Gilks CB, et al.: Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol 29 (16): 2247-52, 2011. [PUBMED Abstract]
- Engel C, Rahner N, Schulmann K, et al.: Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 8 (2): 174-82, 2010. [PUBMED Abstract]
- Reitmair AH, Cai JC, Bjerknes M, et al.: MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res 56 (13): 2922-6, 1996. [PUBMED Abstract]
- Järvinen HJ, Aarnio M, Mustonen H, et al.: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118 (5): 829-34, 2000. [PUBMED Abstract]
- Järvinen HJ, Mecklin JP, Sistonen P: Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 108 (5): 1405-11, 1995. [PUBMED Abstract]
- Voskuil DW, Vasen HF, Kampman E, et al.: Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC. Int J Cancer 72 (2): 205-9, 1997. [PUBMED Abstract]
- Heinimann K, Müller H, Weber W, et al.: Disease expression in Swiss hereditary non-polyposis colorectal cancer (HNPCC) kindreds. Int J Cancer 74 (3): 281-5, 1997. [PUBMED Abstract]
- Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997. [PUBMED Abstract]
- Johnson PM, Gallinger S, McLeod RS: Surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer: an evidence-based review. Dis Colon Rectum 49 (1): 80-93; discussion 94-5, 2006. [PUBMED Abstract]
- Lindor NM, Petersen GM, Hadley DW, et al.: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296 (12): 1507-17, 2006. [PUBMED Abstract]
- Friedman GD, Collen MF, Fireman BH: Multiphasic Health Checkup Evaluation: a 16-year follow-up. J Chronic Dis 39 (6): 453-63, 1986. [PUBMED Abstract]
- Mecklin JP, Aarnio M, Läärä E, et al.: Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 133 (4): 1093-8, 2007. [PUBMED Abstract]
- Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, et al.: Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol 27 (28): 4793-7, 2009. [PUBMED Abstract]
- Hurlstone DP, Karajeh M, Cross SS, et al.: The role of high-magnification-chromoscopic colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective "back-to-back" endoscopic study. Am J Gastroenterol 100 (10): 2167-73, 2005. [PUBMED Abstract]
- Lecomte T, Cellier C, Meatchi T, et al.: Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome. Clin Gastroenterol Hepatol 3 (9): 897-902, 2005. [PUBMED Abstract]
- Rodríguez-Bigas MA, Vasen HF, Pekka-Mecklin J, et al.: Rectal cancer risk in hereditary nonpolyposis colorectal cancer after abdominal colectomy. International Collaborative Group on HNPCC. Ann Surg 225 (2): 202-7, 1997. [PUBMED Abstract]
- Vasen HF, Möslein G, Alonso A, et al.: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44 (6): 353-62, 2007. [PUBMED Abstract]
- Burn J, Gerdes AM, Macrae F, et al.: Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378 (9809): 2081-7, 2011. [PUBMED Abstract]
- Burn J, Bishop DT, Mecklin JP, et al.: Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 359 (24): 2567-78, 2008. [PUBMED Abstract]
- Hampel H, Frankel W, Panescu J, et al.: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66 (15): 7810-7, 2006. [PUBMED Abstract]
- Westin SN, Lacour RA, Urbauer DL, et al.: Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol 26 (36): 5965-71, 2008. [PUBMED Abstract]
- Ng AB, Reagan JW, Hawliczek S, et al.: Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 18 (5): 356-61, 1974 Sep-Oct. [PUBMED Abstract]
- Yancey M, Magelssen D, Demaurez A, et al.: Classification of endometrial cells on cervical cytology. Obstet Gynecol 76 (6): 1000-5, 1990. [PUBMED Abstract]
- Dove-Edwin I, Boks D, Goff S, et al.: The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 94 (6): 1708-12, 2002. [PUBMED Abstract]
- Rijcken FE, Mourits MJ, Kleibeuker JH, et al.: Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 91 (1): 74-80, 2003. [PUBMED Abstract]
- Renkonen-Sinisalo L, Bützow R, Leminen A, et al.: Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 120 (4): 821-4, 2007. [PUBMED Abstract]
- Yang K, Allen B, Conrad P, et al.: Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families. Fam Cancer 5 (4): 405-9, 2006. [PUBMED Abstract]
- Collins VR, Meiser B, Ukoumunne OC, et al.: The impact of predictive genetic testing for hereditary nonpolyposis colorectal cancer: three years after testing. Genet Med 9 (5): 290-7, 2007. [PUBMED Abstract]
- Parry S, Win AK, Parry B, et al.: Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 60 (7): 950-7, 2011. [PUBMED Abstract]
- de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, et al.: Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut 52 (12): 1752-5, 2003. [PUBMED Abstract]
- Natarajan N, Watson P, Silva-Lopez E, et al.: Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis Colon Rectum 53 (1): 77-82, 2010. [PUBMED Abstract]
- Maeda T, Cannom RR, Beart RW Jr, et al.: Decision model of segmental compared with total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer. J Clin Oncol 28 (7): 1175-80, 2010. [PUBMED Abstract]
- Lee JS, Petrelli NJ, Rodriguez-Bigas MA: Rectal cancer in hereditary nonpolyposis colorectal cancer. Am J Surg 181 (3): 207-10, 2001. [PUBMED Abstract]
- Kalady MF, Lipman J, McGannon E, et al.: Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann Surg 255 (6): 1121-5, 2012. [PUBMED Abstract]
- Olsen KØ, Juul S, Bülow S, et al.: Female fecundity before and after operation for familial adenomatous polyposis. Br J Surg 90 (2): 227-31, 2003. [PUBMED Abstract]
- Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24 (28): 4642-60, 2006. [PUBMED Abstract]
- Vasen HF, Blanco I, Aktan-Collan K, et al.: Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62 (6): 812-23, 2013. [PUBMED Abstract]
- Rodriguez-Bigas MA, Möeslein G: Surgical treatment of hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). Fam Cancer 12 (2): 295-300, 2013. [PUBMED Abstract]
- Hurlstone DP, Cross SS, Slater R, et al.: Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy. Gut 53 (3): 376-80, 2004. [PUBMED Abstract]
- Saitoh Y, Waxman I, West AB, et al.: Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 120 (7): 1657-65, 2001. [PUBMED Abstract]
- Hurlstone DP, Cross SS, Adam I, et al.: Endoscopic morphological anticipation of submucosal invasion in flat and depressed colorectal lesions: clinical implications and subtype analysis of the kudo type V pit pattern using high-magnification-chromoscopic colonoscopy. Colorectal Dis 6 (5): 369-75, 2004. [PUBMED Abstract]
- Dacosta RS, Wilson BC, Marcon NE: New optical technologies for earlier endoscopic diagnosis of premalignant gastrointestinal lesions. J Gastroenterol Hepatol 17 (Suppl): S85-104, 2002. [PUBMED Abstract]
- Rembacken BJ, Fujii T, Cairns A, et al.: Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 355 (9211): 1211-4, 2000. [PUBMED Abstract]
- Tsuda S, Veress B, Tóth E, et al.: Flat and depressed colorectal tumours in a southern Swedish population: a prospective chromoendoscopic and histopathological study. Gut 51 (4): 550-5, 2002. [PUBMED Abstract]
- Rex DK, Helbig CC: High yields of small and flat adenomas with high-definition colonoscopes using either white light or narrow band imaging. Gastroenterology 133 (1): 42-7, 2007. [PUBMED Abstract]
- Soetikno RM, Kaltenbach T, Rouse RV, et al.: Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 299 (9): 1027-35, 2008. [PUBMED Abstract]
- Stoffel EM, Turgeon DK, Stockwell DH, et al.: Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying. Cancer Prev Res (Phila) 1 (7): 507-13, 2008. [PUBMED Abstract]
- Le Rhun M, Coron E, Parlier D, et al.: High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study. Clin Gastroenterol Hepatol 4 (3): 349-54, 2006. [PUBMED Abstract]
- Brooker JC, Saunders BP, Shah SG, et al.: Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc 56 (3): 333-8, 2002. [PUBMED Abstract]
- Stoffel EM, Turgeon DK, Stockwell DH, et al.: Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res (Phila) 1 (6): 470-5, 2008. [PUBMED Abstract]
- Hüneburg R, Lammert F, Rabe C, et al.: Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening. Endoscopy 41 (4): 316-22, 2009. [PUBMED Abstract]
- Wallace MH, Frayling IM, Clark SK, et al.: Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 42 (8): 1078-80, 1999. [PUBMED Abstract]
- Dekker E, Boparai KS, Poley JW, et al.: High resolution endoscopy and the additional value of chromoendoscopy in the evaluation of duodenal adenomatosis in patients with familial adenomatous polyposis. Endoscopy 41 (8): 666-9, 2009. [PUBMED Abstract]
- Sakamoto H, Yamamoto H, Hayashi Y, et al.: Nonsurgical management of small-bowel polyps in Peutz-Jeghers syndrome with extensive polypectomy by using double-balloon endoscopy. Gastrointest Endosc 74 (2): 328-33, 2011. [PUBMED Abstract]
- Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994. [PUBMED Abstract]
- Slattery ML, Kerber RA: Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 86 (21): 1618-26, 1994. [PUBMED Abstract]
- Butterworth AS, Higgins JP, Pharoah P: Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 42 (2): 216-27, 2006. [PUBMED Abstract]
- St John DJ, McDermott FT, Hopper JL, et al.: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118 (10): 785-90, 1993. [PUBMED Abstract]
- Zauber AG, Bond JH, Winawer SJ: Surveillance of patients with colorectal adenomas or cancer. In: Young GP, Rozen P, Levin B, eds.: Prevention and Early Detection of Colorectal Cancer. London, England: WB Saunders, 1996, pp 195-215.
- Winawer SJ, Zauber AG, Gerdes H, et al.: Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 334 (2): 82-7, 1996. [PUBMED Abstract]
- Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348 (10): 919-32, 2003. [PUBMED Abstract]
- Lichtenstein P, Holm NV, Verkasalo PK, et al.: Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 (2): 78-85, 2000. [PUBMED Abstract]
- Hemminki K, Chen B: Familial risk for colorectal cancers are mainly due to heritable causes. Cancer Epidemiol Biomarkers Prev 13 (7): 1253-6, 2004. [PUBMED Abstract]
- Woolf CM: A genetic study of carcinoma of the large intestine. Am J Hum Genet 10 (1): 42-7, 1958. [PUBMED Abstract]
- Negri E, Braga C, La Vecchia C, et al.: Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 77 (1): 174-9, 1998. [PUBMED Abstract]
- Duncan JL, Kyle J: Family incidence of carcinoma of the colon and rectum in north-east Scotland. Gut 23 (2): 169-71, 1982. [PUBMED Abstract]
- Rozen P, Fireman Z, Figer A, et al.: Family history of colorectal cancer as a marker of potential malignancy within a screening program. Cancer 60 (2): 248-54, 1987. [PUBMED Abstract]
- Houlston RS, Murday V, Harocopos C, et al.: Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic. BMJ 301 (6748): 366-8, 1990 Aug 18-25. [PUBMED Abstract]
- Cannon-Albright LA, Skolnick MH, Bishop DT, et al.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 319 (9): 533-7, 1988. [PUBMED Abstract]
- Burt RW, Bishop DT, Cannon LA, et al.: Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 312 (24): 1540-4, 1985. [PUBMED Abstract]
- Wiesner GL, Daley D, Lewis S, et al.: A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2. Proc Natl Acad Sci U S A 100 (22): 12961-5, 2003. [PUBMED Abstract]
- Djureinovic T, Skoglund J, Vandrovcova J, et al.: A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer. Gut 55 (3): 362-6, 2006. [PUBMED Abstract]
- Mueller-Koch Y, Vogelsang H, Kopp R, et al.: Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54 (12): 1733-40, 2005. [PUBMED Abstract]
- Llor X, Pons E, Xicola RM, et al.: Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 11 (20): 7304-10, 2005. [PUBMED Abstract]
- Valle L, Perea J, Carbonell P, et al.: Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol 25 (7): 781-6, 2007. [PUBMED Abstract]
- Jass JR: Hereditary Non-Polyposis Colorectal Cancer: the rise and fall of a confusing term. World J Gastroenterol 12 (31): 4943-50, 2006. [PUBMED Abstract]
- Nieminen TT, O'Donohue MF, Wu Y, et al.: Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology 147 (3): 595-598.e5, 2014. [PUBMED Abstract]
- Nieminen TT, Abdel-Rahman WM, Ristimäki A, et al.: BMPR1A mutations in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology 141 (1): e23-6, 2011. [PUBMED Abstract]
- Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 56 (1): 11-25; quiz 49-50, 2006 Jan-Feb. [PUBMED Abstract]
- Levin B, Lieberman DA, McFarland B, et al.: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58 (3): 130-60, 2008 May-Jun. [PUBMED Abstract]
- U.S. Preventive Services Task Force: Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 149 (9): 627-37, 2008. [PUBMED Abstract]
- Rex DK, Johnson DA, Anderson JC, et al.: American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 104 (3): 739-50, 2009. [PUBMED Abstract]
- Zhou XP, Waite KA, Pilarski R, et al.: Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73 (2): 404-11, 2003. [PUBMED Abstract]
- Mester J, Eng C: When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet 163C (2): 114-21, 2013. [PUBMED Abstract]
- Eng C: PTEN: one gene, many syndromes. Hum Mutat 22 (3): 183-98, 2003. [PUBMED Abstract]
- Marsh DJ, Kum JB, Lunetta KL, et al.: PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8 (8): 1461-72, 1999. [PUBMED Abstract]
- Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004. [PUBMED Abstract]
- Eng C: PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, WA: University of Washington, 2013, pp. Available online. Last accessed August 28, 2014.
- Pilarski R, Burt R, Kohlman W, et al.: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 105 (21): 1607-16, 2013. [PUBMED Abstract]
- Tan MH, Mester JL, Ngeow J, et al.: Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 18 (2): 400-7, 2012. [PUBMED Abstract]
- Bubien V, Bonnet F, Brouste V, et al.: High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 50 (4): 255-63, 2013. [PUBMED Abstract]
- Heald B, Mester J, Rybicki L, et al.: Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology 139 (6): 1927-33, 2010. [PUBMED Abstract]
- Peutz JL: Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921.
- Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med 241 (26): 1031-6, 1949. [PUBMED Abstract]
- Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989. [PUBMED Abstract]
- Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005. [PUBMED Abstract]
- Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998. [PUBMED Abstract]
- Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998. [PUBMED Abstract]
- Boudeau J, Kieloch A, Alessi DR, et al.: Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Hum Mutat 21 (2): 172, 2003. [PUBMED Abstract]
- Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003. [PUBMED Abstract]
- Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000. [PUBMED Abstract]
- Lim W, Olschwang S, Keller JJ, et al.: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126 (7): 1788-94, 2004. [PUBMED Abstract]
- van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010. [PUBMED Abstract]
- Srivatsa PJ, Keeney GL, Podratz KC: Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz-Jeghers syndrome. Gynecol Oncol 53 (2): 256-64, 1994. [PUBMED Abstract]
- Scully RE: Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25 (5): 1107-21, 1970. [PUBMED Abstract]
- Westerman AM, Entius MM, de Baar E, et al.: Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353 (9160): 1211-5, 1999. [PUBMED Abstract]
- Mehenni H, Resta N, Park JG, et al.: Cancer risks in LKB1 germline mutation carriers. Gut 55 (7): 984-90, 2006. [PUBMED Abstract]
- Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998. [PUBMED Abstract]
- Wang ZJ, Ellis I, Zauber P, et al.: Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol 188 (1): 9-13, 1999. [PUBMED Abstract]
- Miyoshi H, Nakau M, Ishikawa TO, et al.: Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62 (8): 2261-6, 2002. [PUBMED Abstract]
- Nakau M, Miyoshi H, Seldin MF, et al.: Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62 (16): 4549-53, 2002. [PUBMED Abstract]
- Takeda H, Miyoshi H, Kojima Y, et al.: Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. Oncogene 25 (12): 1816-20, 2006. [PUBMED Abstract]
- Amos CI, Keitheri-Cheteri MB, Sabripour M, et al.: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41 (5): 327-33, 2004. [PUBMED Abstract]
- Latchford AR, Neale K, Phillips RK, et al.: Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum 55 (10): 1038-43, 2012. [PUBMED Abstract]
- Veale AM, McColl I, Bussey HJ, et al.: Juvenile polyposis coli. J Med Genet 3 (1): 5-16, 1966. [PUBMED Abstract]
- Chow E, Macrae F: A review of juvenile polyposis syndrome. J Gastroenterol Hepatol 20 (11): 1634-40, 2005. [PUBMED Abstract]
- Jass JR, Williams CB, Bussey HJ, et al.: Juvenile polyposis--a precancerous condition. Histopathology 13 (6): 619-30, 1988. [PUBMED Abstract]
- Howe JR, Roth S, Ringold JC, et al.: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 (5366): 1086-8, 1998. [PUBMED Abstract]
- Howe JR, Bair JL, Sayed MG, et al.: Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28 (2): 184-7, 2001. [PUBMED Abstract]
- Zhou XP, Woodford-Richens K, Lehtonen R, et al.: Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 69 (4): 704-11, 2001. [PUBMED Abstract]
- Brosens LA, van Hattem A, Hylind LM, et al.: Risk of colorectal cancer in juvenile polyposis. Gut 56 (7): 965-7, 2007. [PUBMED Abstract]
- Gallione CJ, Repetto GM, Legius E, et al.: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363 (9412): 852-9, 2004. [PUBMED Abstract]
- Lesca G, Burnichon N, Raux G, et al.: Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat 27 (6): 598, 2006. [PUBMED Abstract]
- Gallione CJ, Richards JA, Letteboer TG, et al.: SMAD4 mutations found in unselected HHT patients. J Med Genet 43 (10): 793-7, 2006. [PUBMED Abstract]
- Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 44 (11): 702-9, 2007. [PUBMED Abstract]
- O'Malley M, LaGuardia L, Kalady MF, et al.: The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum 55 (8): 886-92, 2012. [PUBMED Abstract]
- Schwenter F, Faughnan ME, Gradinger AB, et al.: Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol 47 (7): 795-804, 2012. [PUBMED Abstract]
- Dahdaleh FS, Carr JC, Calva D, et al.: Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet 81 (2): 110-6, 2012. [PUBMED Abstract]
- Calva-Cerqueira D, Chinnathambi S, Pechman B, et al.: The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet 75 (1): 79-85, 2009. [PUBMED Abstract]
- van Hattem WA, Brosens LA, de Leng WW, et al.: Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 57 (5): 623-7, 2008. [PUBMED Abstract]
- Sweet K, Willis J, Zhou XP, et al.: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294 (19): 2465-73, 2005. [PUBMED Abstract]
- Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003. [PUBMED Abstract]
- Cybulski C, Górski B, Huzarski T, et al.: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75 (6): 1131-5, 2004. [PUBMED Abstract]
- de Jong MM, Nolte IM, Te Meerman GJ, et al.: Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 43 (4): 377-82, 2005. [PUBMED Abstract]
- Cybulski C, Wokołorczyk D, Kładny J, et al.: Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations? Eur J Hum Genet 15 (2): 237-41, 2007. [PUBMED Abstract]
- Suchy J, Cybulski C, Wokołorczyk D, et al.: CHEK2 mutations and HNPCC-related colorectal cancer. Int J Cancer 126 (12): 3005-9, 2010. [PUBMED Abstract]
- Jaeger EE, Woodford-Richens KL, Lockett M, et al.: An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am J Hum Genet 72 (5): 1261-7, 2003. [PUBMED Abstract]
- Thomas HJ, Whitelaw SC, Cottrell SE, et al.: Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q. Am J Hum Genet 58 (4): 770-6, 1996. [PUBMED Abstract]
- Jaeger E, Leedham S, Lewis A, et al.: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 44 (6): 699-703, 2012. [PUBMED Abstract]
- Jass J: Hyperplastic Polyposis. In: Hamilton SR, Aaltonen LA: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2000, pp 135-6.
- Boparai KS, Reitsma JB, Lemmens V, et al.: Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut 59 (9): 1222-5, 2010. [PUBMED Abstract]
- Chow E, Lipton L, Lynch E, et al.: Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 131 (1): 30-9, 2006. [PUBMED Abstract]
- Lage P, Cravo M, Sousa R, et al.: Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study. Am J Gastroenterol 99 (9): 1779-84, 2004. [PUBMED Abstract]
- Leggett BA, Devereaux B, Biden K, et al.: Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25 (2): 177-84, 2001. [PUBMED Abstract]
- Rashid A, Houlihan PS, Booker S, et al.: Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119 (2): 323-32, 2000. [PUBMED Abstract]
- Place RJ, Simmang CL: Hyperplastic-adenomatous polyposis syndrome. J Am Coll Surg 188 (5): 503-7, 1999. [PUBMED Abstract]
- Hyman NH, Anderson P, Blasyk H: Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum 47 (12): 2101-4, 2004. [PUBMED Abstract]
- Koide N, Saito Y, Fujii T, et al.: A case of hyperplastic polyposis of the colon with adenocarcinomas in hyperplastic polyps after long-term follow-up. Endoscopy 34 (6): 499-502, 2002. [PUBMED Abstract]
- Jeevaratnam P, Cottier DS, Browett PJ, et al.: Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 179 (1): 20-5, 1996. [PUBMED Abstract]
- Bengoechea O, Martínez-Peñuela JM, Larrínaga B, et al.: Hyperplastic polyposis of the colorectum and adenocarcinoma in a 24-year-old man. Am J Surg Pathol 11 (4): 323-7, 1987. [PUBMED Abstract]
- McCann BG: A case of metaplastic polyposis of the colon associated with focal adenomatous change and metachronous adenocarcinomas. Histopathology 13 (6): 700-2, 1988. [PUBMED Abstract]
- Kokko A, Laiho P, Lehtonen R, et al.: EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis. BMC Cancer 6: 145, 2006. [PUBMED Abstract]
- Beach R, Chan AO, Wu TT, et al.: BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Am J Pathol 166 (4): 1069-75, 2005. [PUBMED Abstract]
- Burt R, Neklason DW: Genetic testing for inherited colon cancer. Gastroenterology 128 (6): 1696-716, 2005. [PUBMED Abstract]
- McGrath DR, Spigelman AD: Preventive measures in Peutz-Jeghers syndrome. Fam Cancer 1 (2): 121-5, 2001. [PUBMED Abstract]
- Giardiello FM, Trimbath JD: Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 4 (4): 408-15, 2006. [PUBMED Abstract]
- Brosens LA, van Hattem WA, Jansen M, et al.: Gastrointestinal polyposis syndromes. Curr Mol Med 7 (1): 29-46, 2007. [PUBMED Abstract]
- Zbuk KM, Eng C: Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol 4 (9): 492-502, 2007. [PUBMED Abstract]