The WNT/
beta-catenin pathway is involved in numerous human
cancers. Mutations of the CTNNB1 (
beta-catenin) gene have also been detected in a subset of pediatric Wilms
tumors, but the target genes of the deregulated WNT/
beta-catenin pathway in these
tumors have yet to be identified. To compare gene expression profiles of Wilms
tumors with and without mutations of CTNNB1, we used 11.5-k
cDNA microarrays. Most of the
tumors (86%) had received preoperative
chemotherapy as mandated by the European
SIOP protocol. The comparison between Wilms
tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms
tumors. Among these, PITX2, APCDD1, and two members of the
endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/
beta-catenin pathway that may enhance proliferation of these
tumor cells. In addition, several upstream inhibitors of WNT/
beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms
tumors. This overexpression may be a negative feedback mechanism in
tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the
retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms
tumors corresponded to histologically detectable areas of myomatous cells in these
tumors that displayed intense and preferential nuclear
beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.