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.
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.[33,34] 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.[35,36]
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 (LOH), 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 LOH or loss of imprinting at 11p15.5. The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[30,38] 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.[11,12,13] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the NWTS.[13,43,44]