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Frequent Association of ß-Catenin and WT1 Mutations in Wilms Tumors¹

Department of Biochemistry and Molecular Biology [S. M.], Department of Epidemiology [C. I. A.], and Division of Pediatrics [R. A., V. H.], M. D. Anderson Cancer Center, Houston, Texas 77030

Theetiology of Wilms tumor, an embryonic kidney tumor, is genetically heterogeneous. One Wilms tumor gene, WT1, which encodes a zinc finger transcription factor, is mutated in 10–20% of Wilms tumors, but it is still not clear what critical cellular pathway(s) is affected by these mutations. Recently ß-catenin mutations have been reported in 6 of 40 (15%) of Wilms tumors. ß-catenin is the central effector in the Wnt signal transduction pathway, and deregulation of ß-catenin signaling is critical in the development of a number of malignancies. The observation of ß-catenin mutations 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 mutations vis-à-vis ß-catenin mutations in Wilms tumor, we analyzed 153 primary tumors, and 21 of 153 (14%) carried ß-catenin mutations. Surprisingly, we observed a highly significant (P = 3.6 x 10^-13) association between WT1 and ß-catenin mutations; 19 of 20 ß-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 that mutation of WT1 and ß-catenin affects two different cellular pathways, both of which are critically altered in at least a subset of Wilms tumors.

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