Abstract 4349: The tumor suppressor WTX is inactivated in a subset of pediatric tumors

Abstract

Abstract WTX is a recently identified tumor suppressor gene that is expressed during embryonic kidney development and that is inactivated by deletions and truncations in approximately 30% of Wilms tumors, the most common pediatric kidney cancer. Initial functional studies point to a role for this gene in Wnt signaling and WT1 mediated transcription. Given that WTX is also present in a variety of other tissues during development, we tested for potential involvement of WTX in other pediatric tumors. 25 hepatoblastomas, 87 rhabdomyosarcomas, 11 adrenocortical carcinomas, 15 pleuropulmonary blastomas, 30 neuroblastomas and 30 medulloblastomas were tested by 3 color- fluorescence in situ hybridization (FISH) with probes corresponding to WTX (Xq11.1) and two flanking control sites. Discrete WTX deletions were identified in two cases, one hepatoblastoma and one rhabdomyosarcoma, and not in matched control tissues. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas, 27 rhabdomyosarcomas and 11 adrenocortical carcinomas did not reveal point mutations in these tumor types. CTNNB1 exon 3 mutations, which are present in Wilms tumor but generally do not overlap with WTX inactivation, were detected in 8 of 25 hepatoblastomas but not in the tumor with a WTX deletion. Our results indicate that WTX inactivation is a genetic event that occurs in other pediatric malignancies, albeit at a lower frequency than in Wilms tumors. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, constitute a subset of pediatric tumors that are linked to abnormalities of the IGF2 locus on 11p15 in the Beckwith-Wiedemann overgrowth syndrome. Finally, the high frequency of WTX inactivation in Wilms tumors compared to other pediatric malignancies, points to the specificity of the connection between WTX and the kidney developmental pathways that are dysregulated in this disease. 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 4349. doi:10.1158/1538-7445.AM2011-4349