Wilms' tumor causes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
The casue of wilms' tumor is genetic mutations.
Causes
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. Several genes, but not all, will be discussed here.
Aberrations in germline or clonal WT1, WT2, and Wnt activation when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among Wilms tumors.
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.
When modern molecular genetic techniques are used in testing, the incidence of germline WT1 mutations is about 11%. Most of these mutations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. In a United Kingdom Children's Cancer Study Group study of patients entered in clinical trials, about 2% of Wilms tumor patients had germline mutations in WT1 but no genitourinary abnormalities, as detected by WT1 heteroduplex DNA screen followed by sequencing.[37] These were mostly de novo mutations in children presenting before age 2 years, and the tumors were mostly unilateral with stromal histology. The relatively low number of reports of parent and child pairs with Wilms tumors and WT1 mutations may be the result of decreased fertility. However, the offspring of a child who has a parent with Wilms tumor and WT1 mutation will be at risk for developing Wilms tumor.
Germline WT1 mutations in children with Wilms tumors do not confer poor prognoses per se.
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 Denys-Drash syndrome.
WT1 mutations are more common in children with Wilms tumor and one of the following:
- WAGR syndrome, Denys-Drash syndrome,[14] or Frasier syndrome.[11]
- Genitourinary anomalies, including hypospadias and cryptorchidism.
- Bilateral Wilms tumor.
- Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
- Stromal and rhabdomyomatous differentiation.
Imprinting Cluster Regions (ICR) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5, which, when it is a germline mutation, causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[41]
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[57] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele ofCDKNIC, paternal uniparental isodisomy of 11 p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[41,58]
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[58] Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active 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.[41,57,58]
A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[59] The overall tumor risk in patients with Beckwith-Wiedemann syndrome has been estimated between 5% and 10%, with a risk between 1% (loss of imprinting at IC2) and 30% (gain of methylation at IC1 and paternal 11p15 isodisomy). Patients with IC1 gain of methylation only developed Wilms tumor, whereas other tumors such as neuroblastoma or hepatoblastoma could occur in patients with paternal 11p15 isodisomy.[60-62]
Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[63] Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.[64]
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[16-18] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[1,18]
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. This gene is inactivated in approximately one-third of Wilms tumors, but germline mutations have not been observed in patients with Wilms tumor.[65] WTX mutations are equally distributed between males and females. WTX inactivation is a frequent, but late, event in tumorigenesis and has no apparent effect on clinical presentation or prognosis.[66]
Other genes and chromosomal alterations
Additional genes have been implicated in the pathogenesis and biology of Wilms tumor, including the following:
1q: Gain of 1q or overexpression of genes from 1q has been associated with an adverse outcome.
In an analysis of 212 patients from NWTS-4 and the Pediatric Oncology Group Wilms Biology study, 27% of patients displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year event-free survival (EFS) rate was 76% (95% CI, 63%–85%) for patients with 1q gain and 93% (95% CI, 87%–96%) for those lacking 1q gain (P = .0024). The 8-year overall survival (OS) rate was 89% (95% CI, 78%–94%) for those with 1q gain and 98% (95% CI, 94–99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage. After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate, 2.72;P = .0089).[67]
Similar results have been reported by European investigators.[68]
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.[69]
In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival (RFS) and OS rates. Combined loss of 1p and 16q are used to select favorable-histology (FH) Wilms tumor patients for more aggressive therapy in the current COG study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q loss of heterozygosity.[70] An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[71]
These conflicting results may arise from the greater prognostic significance of 1q gain described above. The loss of heterozygosity of 16q and 1p appear to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[67]
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 FH Wilms tumor.[72] 7p21: A consensus region of loss of heterozygosity has been identified in 7p21 containing ten known genes, including two candidate tumor suppressor genes (Mesenchyme homeobox 2 [MEOX2] and Sclerostin domain containing 1 [SOSTDC1]).[73] SKCG-1: Somatic loss of a growth regulatory gene, SKCG-1, located at 11q23.2, was found in 38% of examined sporadic Wilms tumors, particularly the highly proliferative Wilms tumors. Additional studies of siRNA silencing of the SKCG-1 gene in human embryonic kidney epithelial cells resulted in a 40% increase in cell growth, suggesting that this gene may be involved in loss of growth regulation and Wilms tumorigenesis.[74] TP53 (tumor suppressor gene): Most anaplastic Wilms tumors show mutations in the p53 tumor suppressor gene. It may be useful as an unfavorable prognostic marker.[75,76] Microdissection of focally anaplastic Wilms tumors demonstrated TP53 mutation in anaplastic but not nonanaplastic areas of the tumor, suggesting that acquisition of TP53mutation may be inherent in the process of becoming anaplastic.[77] 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.[78] PTCH1: Patients with germline 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor. PTCH1 has a role in the pathogenesis of nephroblastoma. This is supported by the germline deletion of one copy of the PTCH1 gene in all described patients, as well as the presence of a nonsense mutation in the remaining allele in a Wilms tumor of one of the patients.[25] DICER1: Germline mutations in DICER1 have been associated with a pleiotropic tumor predisposition syndrome, and Wilms tumor is a rare manifestation of this syndrome. A subset of Wilms tumors have been reported to exhibit two “hits” in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumors.
The pathology of WT1-associated and DICER1-associated Wilms tumors appears to differ. WT1-associated Wilms tumors are often stromal rich, with rhabdomyomatous differentiation and intralobar nephrogenic rests that are thought to occur early in renal development, while DICER1-associated Wilms tumors are triphasic with abundant blastema and are not associated with nephrogenic rests.[79]
MYCN: Genomic gain or amplification of MYCN is relatively common in Wilms tumors and associated with diffuse anaplastic histology.[78]
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