Medulloblastomas (MBs) represent the most frequent malignant brain tumors of childhood. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin, AXIN1 and Conductin (AXIN2), which cause activation of the Wnt signaling pathway in about 20% of this malignant tumors. The Wnt signaling pathway is negatively controlled by the Wilms tumor suppressor gene WTX, a component of this signaling complex.

To investigate whether alterations in WTX may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the WTX gene in 76 MB biopsy samples and 5 MB cell lines using single-strand conformation polymorphism and sequencing analysis. Two rare WTX single nucleotide polymorphisms (SNPs) c.135C>T in exon 2 of two different MBs (Ser > Ser; TCC >TCT), both of them are not yet known, where identified.

To investigate if the tumor suppressor WTX is regulated in MBs an mRNA expression analysis in 46 MBs and 5 MB cell lines revealed reduced expression of WTX mRNA compared to fetal cerebella tissues. Interestingly, when compared to adult cerebella tissue, WTX is up-regulated in fetal cerebella of different embryonic ages, which indicates a possible involvement of WTX during cerebella development. Moreover, wild-type WTX was found to be over-expressed in tumor cell lines in which the Wnt signaling pathway is activated by mutations in beta-catenin. Our findings indicate that the activation of the Wnt signaling pathway in MBs is not caused by alterations in WTX. However, the down-regulation of WTX could be a possible explanation for the Wnt activation in a subset of MBs. The up-regulation of WTX (related to adult controls) and in particular in Wnt-activated tumor cells suggests that WTX could be a potential target gene of the Wnt signaling pathway, which interacts in a negative feedback loop mechanism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3452. doi:10.1158/1538-7445.AM2011-3452