Abstract 5241: Identifying signaling pathways associated with medulloblastoma subtypes from "omic" data.

Abstract

Abstract Medulloblastoma, the most common malignant pediatric brain tumor, comprises four subtypes classified by their distinct molecular signatures. Wnt and SHH subtypes up-regulate those respective signaling pathways, while Group 3 and Group 4 tumors are less understood and have the worst prognosis. Treatment is currently limited to surgical resection, radiation and broad-spectrum cytotoxic chemotherapy drugs that frequently devastate cognition in survivors. In order to develop patient-specific targeted therapies we need to understand the underlying molecular events that drive the tumor in each patient. Previously, our research group and others sequenced whole exomes from a total 92 primary tumors from patients in comparison to their matched normal blood. Over 1,700 mutated genes were identified. The overwhelming majority of mutations occurred only once in the entire cohort, and just 12 genes were recurrently mutated with statistical significance. Statistically significant mutated genes include genes involved in subtype-specific signaling events, such Wnt and SHH which have been shown to be causative in those subtypes, and others are involved in chromatin and epigenetic regulation. The diversity of mutations makes it difficult to resolve which mutations drive oncogenesis, especially in Groups 3 and 4. Most patients in these subtypes do not harbor a mutation in one of the 12 significantly mutated genes, leaving an open question as to why these patients developed cancer. The aim of this study is to employ systems biology to interweave singleton genes into networks to identify candidate drives in each patient and ultimately resolve the underlying common pathways that caused each cancer. We have identified singleton mutations in patients that substitute for the statically significant mutated genes. Modeling individual patient level data onto networks predicts novel driver events in each patient. These candidate driver events are then functionally validated in vitro. In addition to mutation, oncogenic events can occur via copy number changes, chromatin regulation, transcription regulation, mRNA processing, or protein degradation. We hypothesize that common pathways are targeted in multiple tumors of the same type, despite the obvious differences in the patterns of somatic mutations. Citation Format: Tenley C. Archer, Shyamal Dilhan Weeraratne, Jessica Pierre Francois, Scott L. Pomeroy. Identifying signaling pathways associated with medulloblastoma subtypes from "omic" data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5241. doi:10.1158/1538-7445.AM2013-5241