Frequent association of beta-catenin and WT1 mutations in Wilms tumors

The etiology of Wilms tumor, an embryonic kidney tumor, is genetically hete rogeneous. One Wilms tumor gene, WT1, which encodes a zinc finger transcrip tion factor, is mutated in 10-20% of Wilms tumors, but it is still not clea r what critical cellular pathway (s) is affected by these mutations. Recent ly beta -catenin mutations have been reported in 6 of 40 (15%) of Wilms tum ors, beta -catenin is the central effector in the Wnt signal transduction p athway, and deregulation of beta -catenin signaling is critical in the deve lopment of a number of malignancies. The observation of beta -catenin mutat ions in Wilms tumors suggests that abrogation of the Wnt signaling pathway also plays a role in some Wilms tumors. To assess the relationship of WT1 m utations ris-ci-vis beta -catenin mutations in Wilms tumor,we analyzed 153 primary tumors, and 21 of 153 (14%) carried beta -catenin mutations. Surpri singly, we observed a highly significant (P = 3.6 x 10(-13)) association be tween WT1 and beta -catenin mutations; 19 of 20 beta -catenin-mutant tumors had also sustained WT1 mutations. By analogy to the patterns of concordant and discordant gene mutations observed in other tumors, our data suggest t hat mutation of WT1 and beta -catenin affects two different cellular pathwa ys, both of which are critically altered in at least a subset of Wilms tumo rs.