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From the Institute for Cancer Genetics,* the Department of Pathology, and the Department of Urology, Division of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, New York; the Department of Medicine, Mount Sinai School of Medicine, New York, New York; the Department of Internal Medicine,|| Division of Medical Genetics and the Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; and the Department of Pediatrics, ¶ University of Alberta and Cross Cancer Center, Edmonton, Alberta, Canada
Gain-of-function mutations in exon 3 of ß-catenin (CTNNB1) are specific for Wilms’ tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of ß-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms’ tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms’ tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known ß-catenin/TCF targets (FST, CSPG2, CMYC). ß-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct ß-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms’ tumor, and indicate strong selection for stabilization of ß-catenin in the WT1-mutant class. ß-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.
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