Colon Cancer Genes

Major Genes
Adenomatous Polyposis Coli (APC)
Mut Y Homolog
DNA MMR Genes
Peutz-Jeghers Gene(s)
Juvenile Polyposis Gene(s)
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)
De novo mutation rate

Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.

The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and DNA repair genes.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis, among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome (LS) section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

Several reviews have been published describing the hereditary colon cancer genes.[3-5]

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 attenuated FAP (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.[6,7] AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.[8-11]

More than 300 different disease-associated mutations of the APC gene have been reported.[7] 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.[12]

Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[8-10] 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,[9] and that retinal lesions are rarely associated with mutations that occur before exon 9.[10,13] Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.[14]

The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1.[15] 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, two major variants (Y165C and/or G382D) account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations.[16] Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.[17]

LS is caused by mutation of one of several DNA MMR genes.[18-24] 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;[21,22] MLH1 (mutL homolog 1) on chromosome 3p21;[20] PMS2 (postmeiotic segregation 2) on chromosome 7p22;[24,25] 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.[26,27]

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.[27-32] 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 multiplex ligation-dependent probe amplification (MLPA),[33] for detection of large deletions, are being used.[34] (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.)

Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal polyposis and is caused by mutations in the STK11 (also named LKB1) tumor suppressor gene located on chromosome 19p13.[35,36] Unlike the adenomas seen in FAP, 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.[37,38] 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.[39] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[40] indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.[41]

Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions.[42,43] 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.[42]

One gene (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.[43-45] Given the results of these studies, it is unlikely that other major genes cause PJS.

(Refer to the Peutz-Jeghers syndrome (PJS) section in the Rare Colon Cancer Syndromes section of this summary for more information.)

Juvenile polyposis is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, usually in the setting of a family history. The diagnosis of a juvenile polyp is based on its histologic appearance rather than age of onset, and the familial form is caused by mutations in the BMPR1A gene in 20% of cases and by mutations in the SMAD4 gene in another 20%.[46,47]

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,[48] 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.

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 juvenile polyposis who did not have identifiable mutations in SMAD4. Mutations in BMPR1A include nonsense, frameshift, missense, and splice-site mutations.[49] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome.[50,51] It was reported that two individuals with mutations in both PTEN and BMPR1A also had phenotypic features of juvenile polyposis syndrome (JPS) and Cowden syndrome (see below).[52] Rare JPS families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.[52,53]

JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN.[54]

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.[55]

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.[56] Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[57]

(Refer to the Cowden Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous mutation rate (de novo mutation rate) in these populations. Interestingly, FAP, JPS, PJS, Cowden syndrome, and BRRS are all thought to have high rates of spontaneous mutations, in the 25% to 30% range,[58-60] while estimates of de novo mutations in the MMR genes associated with LS are thought to be low, in the 0.9% to 5% range.[61-63] These estimates of spontaneous mutation rates in LS seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[64-66] making the de novo mutation rate for LS seem quite low in contrast to the relatively high rates in the other polyposis syndromes.

1. Caporaso N, Goldstein A: Cancer genes: single and susceptibility: exposing the difference. Pharmacogenetics 5 (2): 59-63, 1995.  [PUBMED Abstract]
   
   
2. Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 10 (8): 789-99, 2004.  [PUBMED Abstract]
   
   
3. Grady WM, Markowitz SD: Hereditary colon cancer genes. Methods Mol Biol 222: 59-83, 2003.  [PUBMED Abstract]
   
   
4. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348 (10): 919-32, 2003.  [PUBMED Abstract]
   
   
5. Grady WM: Genetic testing for high-risk colon cancer patients. Gastroenterology 124 (6): 1574-94, 2003.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. Nielsen M, Morreau H, Vasen HF, et al.: MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 79 (1): 1-16, 2011.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    
28. 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]
    
    
29. 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]
    
    
30. 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]
    
    
31. 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]
    
    
32. Tomsic J, Liyanarachchi S, Hampel H, et al.: An American founder mutation in MLH1. Int J Cancer 130 (9): 2088-95, 2012.  [PUBMED Abstract]
    
    
33. 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]
    
    
34. Gruber SB: New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 130 (2): 577-87, 2006.  [PUBMED Abstract]
    
    
35. 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]
    
    
36. 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]
    
    
37. Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998.  [PUBMED Abstract]
    
    
38. 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]
    
    
39. 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]
    
    
40. 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]
    
    
41. 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]
    
    
42. 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]
    
    
43. 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]
    
    
44. 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]
    
    
45. 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]
    
    
46. Sayed MG, Ahmed AF, Ringold JR, et al.: Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 9 (9): 901-6, 2002.  [PUBMED Abstract]
    
    
47. Howe JR, Sayed MG, Ahmed AF, et al.: The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 41 (7): 484-91, 2004.  [PUBMED Abstract]
    
    
48. 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]
    
    
49. 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]
    
    
50. 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]
    
    
51. 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]
    
    
52. 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]
    
    
53. 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]
    
    
54. 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]
    
    
55. 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]
    
    
56. Eng C: PTEN: one gene, many syndromes. Hum Mutat 22 (3): 183-98, 2003.  [PUBMED Abstract]
    
    
57. 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]
    
    
58. Aretz S, Uhlhaas S, Caspari R, et al.: Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet 12 (1): 52-8, 2004.  [PUBMED Abstract]
    
    
59. Westerman AM, Entius MM, Boor PP, et al.: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13 (6): 476-81, 1999.  [PUBMED Abstract]
    
    
60. Schreibman IR, Baker M, Amos C, et al.: The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 100 (2): 476-90, 2005.  [PUBMED Abstract]
    
    
61. Morak M, Laner A, Scholz M, et al.: Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer. Eur J Gastroenterol Hepatol 20 (11): 1101-5, 2008.  [PUBMED Abstract]
    
    
62. Plasilova M, Zhang J, Okhowat R, et al.: A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient. Genes Chromosomes Cancer 45 (12): 1106-10, 2006.  [PUBMED Abstract]
    
    
63. Win AK, Jenkins MA, Buchanan DD, et al.: Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48 (8): 530-4, 2011.  [PUBMED Abstract]
    
    
64. Anderson KG: How well does paternity confidence match actual paternity? Evidence from worldwide nonpaternity rates. Curr Anthropol 47 (3): 513-20, 2006. Also available online. Last accessed May 06, 2013. 
    
    
65. Sasse G, Müller H, Chakraborty R, et al.: Estimating the frequency of nonpaternity in Switzerland. Hum Hered 44 (6): 337-43, 1994 Nov-Dec.  [PUBMED Abstract]
    
    
66. Voracek M, Haubner T, Fisher ML: Recent decline in nonpaternity rates: a cross-temporal meta-analysis. Psychol Rep 103 (3): 799-811, 2008.  [PUBMED Abstract]