CTNNB1 mutations and overexpression of Wnt/β-catenin target genes in WT1-mutant wilms' tumors

Chi Ming Li, Connie E. Kim, Adam A. Margolin, Meirong Guo, Jimmy Zhu, Jacqueline M. Mason, Terrence W. Hensle, Vundavalli V.V.S. Murty, Paul E. Grundy, Eric R. Fearon, Vivette D'Agati, Jonathan D. Licht, Benjamin Tycko

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Gain-of-function mutations in exon 3 of β-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 β-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), signalling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known β-catenin/TCF targets (FST, CSPG2, CMYC). β-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 to some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct β-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 β-catenin in the WT1-mutant class. β-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.

Original languageEnglish (US)
Pages (from-to)1943-1953
Number of pages11
JournalAmerican Journal of Pathology
Volume165
Issue number6
DOIs
StatePublished - Dec 2004
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Li, C. M., Kim, C. E., Margolin, A. A., Guo, M., Zhu, J., Mason, J. M., Hensle, T. W., Murty, V. V. V. S., Grundy, P. E., Fearon, E. R., D'Agati, V., Licht, J. D., & Tycko, B. (2004). CTNNB1 mutations and overexpression of Wnt/β-catenin target genes in WT1-mutant wilms' tumors. American Journal of Pathology, 165(6), 1943-1953. https://doi.org/10.1016/S0002-9440(10)63246-4