GENOTYPE PHENOTYPE CORRELATIONS IN WILMS-TUMOR/

Study of genotype/phenotype relationships involving the Wilms' tumor ( WT) gene, WT1, in WI patients has provided insights into the function of the WT1 protein, a transcriptional regulator, and has suggested pos sible mutational mechanisms important in the etiology of WT. for examp le, the identification of deletion/insertion mutations in the first ex on implicates a deletion hotspot consensus sequence in the etiology of these mutations. The disproportionate number of WT/aniridia patients with such mutations further suggest that this genetic mechanism may be enhanced by the hemizygous state. WT1 mutations are observed througho ut the gene and, as predicted by the two-hit mutational model, germlin e mutations predominantly occur in patients with congenital genitourin ary (CU) anomalies and/or bilateral disease. The presence of hemizygou s mutations in tumors from individuals with germline 11p13 deletions e ncompassing WT1 supports the hypothesis that inactivation of both WT1 alleles is important in tumorigenesis. Analyses of WT1 mutations in in dividuals with WT-associated Drash syndrome and WT patients with CU an omalies in the absence of Drash syndrome indicate that Drash patients almost invariably carry germline missense mutations in the zinc finger domains whereas WT/GU patients carry germline mutations that delete t he WT1 gene or encode truncated proteins. These data suggest a functio nal difference between mutant WT1 protein carrying a single amino acid substitution versus mutant WT1 protein that is grossly truncated or W T1 haploinsufficiency. These and other genotype/phentotype correlation s in WT patients will be discussed in more detail. (C) 1996 Wiley-Liss , Inc.