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

Am J Pathol. 2004 Dec;165(6):1943-53. doi: 10.1016/s0002-9440(10)63246-4.


Gain-of-function mutations in exon 3 of beta-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 beta-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 beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-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 beta-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 beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Cytoskeletal Proteins / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kidney / metabolism
  • Kidney Neoplasms / genetics*
  • Luciferases / metabolism
  • Mutation*
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics*
  • Trans-Activators / genetics*
  • Transfection
  • WT1 Proteins / genetics*
  • Wilms Tumor / genetics*
  • Wnt Proteins
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Isoenzymes
  • Proto-Oncogene Proteins
  • Trans-Activators
  • WT1 Proteins
  • Wnt Proteins
  • beta Catenin
  • Luciferases
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1