Table 1. Syndromes and Conditions Associated With Wilms Tumor continued...
The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF (brain-derived neurotrophic factor).
WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy. These findings await validation but may provide biomarkers by which to stratify patients in the future.
WT1interaction with beta-catenin
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.[51,52] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation.[53,54] About one-third of Wilms tumors have a somatic mutation in WT1, WTX, and/or CTNNB1.
Wilms tumor 2locus (WT2)
When modern molecular genetic techniques are used in testing, the incidence of germline WT2 aberrations is about 8%. Most of these aberrations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. However, when 437 children with nonsyndromic Wilms tumor were screened for germline mutations in the WT2 locus, 13 mutations (3% of patients) were found. None of these children had signs of Beckwith-Wiedemann syndrome, although they did have a higher frequency of bilateral tumors and perilobar nephrogenic rests. All were de novo abnormalities, except one novel microdeletion in one child, and their mother was not affected. A similar mutation at the WT2 locus was found in 1 of 22 familial Wilms tumor families tested.
WT2and 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 the 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.