Table 1. Syndromes and Conditions Associated With Wilms Tumor continued...
Genes Associated With Wilms Tumor
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 1gene (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. 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, or Frasier syndrome.
- Genitourinary anomalies, including hypospadias and cryptorchidism.
- Bilateral Wilms tumor.
- Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
- Stromal and rhabdomyomatous differentiation.