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

The WNT/β‐catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (β‐catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/β‐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/β‐catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/β‐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 β‐catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat. © 2006 Wiley‐Liss, Inc.