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.[15,16,17] 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.
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.