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 LOH 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 overall survival 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 LOH 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.[51,52]
- 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.
Genetics of Familial Wilms Tumor
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).[56,57,58]