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Target genes of the WNT/beta-catenin pathway in Wilms tumors

Birgit Zirn1, Birgit Samans, Stefanie Wittmann

  • 1Physiological Chemistry I, Biozentrum, University of Wuerzburg, Germany.

Genes, Chromosomes & Cancer
|April 1, 2006
PubMed

Insights

Pediatric Wilms tumors with CTNNB1 mutations show deregulated WNT/beta-catenin pathway genes, including PITX2 and EDN3, potentially driving tumor growth. Upstream WNT inhibitors are also upregulated, suggesting a feedback loop.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The WNT/beta-catenin pathway is crucial in human cancers.
  • CTNNB1 (beta-catenin) gene mutations occur in pediatric Wilms tumors.
  • Identifying WNT pathway targets in these tumors is essential.

Purpose of the Study:

  • To compare gene expression in Wilms tumors with and without CTNNB1 mutations.
  • To identify specific WNT/beta-catenin pathway target genes deregulated in CTNNB1-mutated Wilms tumors.

Main Methods:

  • Utilized 11.5-k cDNA microarrays for gene expression profiling.
  • Compared tumors with and without CTNNB1 mutations.
  • Most tumors (86%) received preoperative chemotherapy per the European SIOP protocol.

Main Results:

  • Identified deregulated genes in CTNNB1-mutated Wilms tumors, including PITX2, APCDD1, EDN3, and EDNRA, which are activated WNT/beta-catenin targets.
  • Observed upregulation of WNT pathway inhibitors (WIF1, PRDC), suggesting negative feedback.
  • Found deregulated retinoic acid and RAS pathway genes (ATX/ENPP2, RIS1), indicating pathway crosstalk.
  • Noted enrichment of muscle-related genes correlating with myomatous cell presence and beta-catenin staining.

Conclusions:

  • CTNNB1 mutations in Wilms tumors lead to specific WNT/beta-catenin pathway gene deregulation.
  • Activated targets like PITX2 and EDN3 may promote tumor proliferation.
  • Upregulated inhibitors suggest a feedback mechanism.
  • Associations with retinoic acid and RAS pathways warrant further investigation.

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