Congenital Anomalies and Syndromes Predisposing to Wilms Tumor
Screening Children Predisposed to Wilms Tumor
Genetics of Wilms Tumor
Wilms tumor 1 gene (WT1)
Wilms tumor 2 gene (WT2)
Wilms tumor gene on the X chromosome (WTX)
Genetics of Familial Wilms Tumor
Bilateral Wilms Tumor
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2006, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)Prognosis
Wilms tumor is a curable disease in the majority of affected children. Approximately 500 cases are diagnosed in the United States each year. Since the 1980s, the 5-year survival rate for Wilms tumor has been consistently above 90%. This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy. The prognosis for patients with Wilms tumor is related not only to the stage of disease at diagnosis, the histopathologic features of the tumor, patient age, and tumor size, but also to the team approach provided to each patient by the pediatric surgeon, radiation oncologist, and pediatric oncologist (COG-AREN9404).[4-7] Patients who develop Wilms tumor in their second decade of life have a poorer survival (5-year survival, 63%) than younger patients with Wilms tumor.
In an analysis of Wilms tumor patients in the Surveillance, Epidemiology and End Results database, adults (n = 152) had a statistically worse overall survival (OS) (69% vs. 88%, P < .001) than pediatric patients (n = 2,190), despite previous studies showing comparable outcome when treated on protocol.[9,10] Adults with Wilms tumor were more likely than pediatric patients to be staged as having localized disease, to not receive any lymph node sampling, and to not receive any radiation treatment. The investigators recommended that all adult patients diagnosed with Wilms tumor should undergo lymph node sampling and that there should be close collaboration with pediatric surgeons and oncologists in treatment planning. The Children's Oncology Group has increased the enrollment age for their Wilms tumor trials to include patients up to age 30 years.Congenital Anomalies and Syndromes Predisposing to Wilms Tumor
Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have a congenital anomaly. Children with Wilms tumor may have associated urinary tract anomalies, including hemihypertrophy, cryptorchidism, and hypospadias. Children may have a recognizable phenotypic syndrome (including overgrowth disease, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes have been divided into overgrowth and nonovergrowth categories.
- Overgrowth syndromes. Overgrowth syndromes are the result of excessive prenatal and postnatal somatic growth.[13,14] Examples of overgrowth syndromes include the following:
- Beckwith-Wiedemann syndrome (prevalence is about 1% of children with Wilms tumor).[15-18]
- Isolated hemihypertrophy (prevalence is about 2.5% of children with Wilms tumor).[15,19]
- Perlman syndrome (characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation). Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome.
- Sotos syndrome (characterized by cerebral gigantism).
- Simpson-Golabi-Behemel syndrome (characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers).
- Nonovergrowth syndromes. Examples of nonovergrowth syndromes associated with Wilms tumor include the following:
- WAGR syndrome (aniridia, genitourinary anomaly, and mental retardation). The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del[11p13]).[22,23] (prevalence is about 0.4% of children with Wilms tumor). The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%.
- Isolated aniridia.
- Genitourinary anomalies including hypospadias, undescended testis, and others are associated with Wilms tumor 1 (WT1) mutations (prevalence is over 6% of children with Wilms tumor). Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have the Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities), both of which are associated with mutations in the WT1 gene. Specifically, germline missense mutations in the WT1 gene are responsible for most Wilms tumors that occur as part of the Denys-Drash syndrome.[27,28]
- Bloom syndrome.
- Alagille syndrome.
- Trisomy 18.
- Li-Fraumeni syndrome (familial cancer syndrome).
Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome, WAGR syndrome, Denys-Drash syndrome, idiopathic hemihypertrophy, or sporadic aniridia) should be screened with ultrasound every 3 months at least until they reach age 8 years.[13-15,30]
Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with either Wilms tumor or hepatoblastoma being the most common, although adrenal tumors can also occur. Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years; after age 4, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require the child to fast for the exam.
Children with Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, had been considered to be at increased risk for developing Wilms tumor. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome, when assessed using the National Wilms Tumor Study (NWTS) database, was no different than in the general population and routine ultrasound surveillance is not recommended.Genetics of Wilms Tumor
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. Several, but not all, will be discussed here.Wilms tumor 1 gene (WT1)
The WT1 gene is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema. Germline mutations in WT1 have been found in about 2% of phenotypically normal children with Wilms tumor. Germline WT1 mutations in children with Wilms tumor does not confer a poor prognosis per se. The offspring of those with germline mutation in WT1 may also be at increased risk of developing Wilms tumor. Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in the Denys-Drash syndrome.
WT1 mutation is more common in those children with Wilms tumor and one of the following:
- WAGR syndrome, Denys-Drash syndrome, or sporadic aniridia.
- Genitourinary anomalies, including hypospadias and cryptorchidism.
- Bilateral Wilms tumor.
- Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
- Stromal and rhabdomyomatous differentiation.
The observation that lead to the discovery of WT1 was that children with WAGR syndrome (aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene (responsible for aniridia). Aniridia is characterized by hypoplasia of the iris and it occurs in sporadic or familial cases and has an autosomal dominant inheritance. Mutations in the PAX6 gene lead to aniridia. The PAX6 gene is located on chromosome 13 closely associated with the WT1 gene, deletion of which confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include the Wilms tumor gene – WT1. This results in an increased relative risk of 67-fold (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk for developing Wilms tumor. Children with familial aniridia generally have a normal WT1 gene and are not at an increased risk of Wilms tumor. The mental retardation in WAGR syndrome may be secondary to deletion of other genes including SLC1A2 or BDNF (brain-derived neurotrophic factor).
The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Patients with sporadic aniridia should be screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1.[15,30]Monitoring for late renal failure
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of eventually developing hypertension, nephropathy, and renal failure and should be monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored. Features associated with germline WT1 mutations that increase the risk for developing renal failure are stromal predominant histology, bilaterality, intralobular nephrogenic rests, and Wilms tumor diagnosed before age 2 years.WT1 interactions
Activating mutations of the beta-catenin gene (CTNNB1) have been reported to occur in 15% of Wilms tumor patients. In one study, all but one tumor with a beta-catenin mutation had a WT1 mutation and at least 50% of the tumors with WT1 mutations had a beta-catenin mutation.[39,40] That CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation suggests that activation of beta-catenin in the presence of intact WT1 protein must be inadequate to promote tumor development.[41,42]
WT1 mutations and 11p15 loss of heterozygosity are associated with relapse in patients with very low-risk Wilms tumor who do not receive chemotherapy. These may provide biomarkers to stratify patients in the future.Wilms tumor 2 gene (WT2)
A second Wilms tumor locus, WT2 gene, maps to an imprinted region of chromosome 11p15.5, which, when constitutional, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have constitutional epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. These children may be more likely to have bilateral Wilms tumor or familial Wilms tumor. There are several candidate genes at the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1. Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally inactive ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have somatic loss of heterozygosity or loss of imprinting at 11p15.5. The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[36,44] Loss of imprinting or gene methylation are rarely found at other loci, supporting the specificity of loss of imprinting at IGF2. Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.
Beckwith-Wiedemann syndrome results from constitutional loss of imprinting or heterozygosity of WT2. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing levels of association with risk of tumor formation. Molecularly defined subsets of Beckwith-Wiedemann patients may not require ultrasound screening for malignancies. Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous bilateral disease is also observed.[15-17] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the NWTS.[17,49,50]Wilms tumor gene on the X chromosome (WTX)
A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. WTX mutations were identified in 17% of Wilms tumors, equally distributed between males and females. This gene is inactivated in approximately one-third of Wilms tumors but germline mutations have not been observed in patients with Wilms tumor.Other genes
Additional genes have been implicated in the pathogenesis and biology of Wilms tumor:
- 16q and 1p: Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumors, respectively. Patients classified by tumor-specific loss of these loci had significantly worse relapse-free and OS rates. Combined loss of 1p and 16q are used to select favorable-histology Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group study.
- CACNA1E: Overexpression and amplification of the gene CACNA1E located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, may be associated with relapse in favorable-histology Wilms tumor.
- 7p21: A consensus region of loss of heterozygosity has been identified within 7p21 containing ten known genes, including two candidate suppressor genes (Mesenchyme homeobox 2 [MEOX2] and Sclerostin domain containing 1 [SOSTDC1]).
- SKCG-1: Genomic loss of a growth regulatory gene, SKCG-1, located at 11q23.2, was found in 38% of examined sporadic Wilms tumors and particularly the highly proliferative Wilms tumors. Additional studies of si-RNA silencing of the SKCG-1 gene in human embryonic kidney epithelial cells resulted in a 40% increase in cell growth, which suggests that this gene may be involved in loss of growth regulation and Wilms tumorigenesis.
- p53 tumor suppressor gene: A small subset of anaplastic Wilms tumors show mutations in the p53 tumor suppressor gene. Although it is unlikely that it plays a major role in Wilms tumorigenesis, it may be useful as an unfavorable prognostic marker.[57,58]
- FBXW7: FBXW7, a ubiquitin ligase component, has been identified as a novel Wilms tumor gene. Mutations of this gene have been associated with epithelial-type tumor histology.
- MYCN: Genomic gain or amplification of MYCN is relatively common in Wilms tumors and associated with diffuse anaplastic histology.
Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a low likelihood of developing Wilms tumor. The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%. Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[62-64]Bilateral Wilms Tumor
About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary. Many bilateral tumors are present at the time Wilms tumor is first diagnosed (i.e., synchronous), but a second Wilms tumor may also develop later in the remaining kidney of 1% to 3% of children treated successfully for Wilms tumor. The incidence of such metachronous bilateral Wilms tumors is much higher in children whose original Wilms tumor was diagnosed before age 12 months and/or whose resected kidney contains nephrogenic rests. Periodic abdominal ultrasound is recommended for early detection of metachronous bilateral Wilms tumor as follows:[63,64]
- Children with nephrogenic rests in the resected kidney (if younger than 48 months at initial diagnosis)—every 3 months for 6 years.
- Children with nephrogenic rests in the resected kidney (if older than 48 months at initial diagnosis)—every 3 months for 4 years.
- Other patients—every 3 months for 2 years, then yearly for an additional 1 to 3 years.
Clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor.[66,67] (Refer to the Cellular Classification section of this summary for more information.)References
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