Abstract B2-21: Identification of somatic RNA splicing alterations in human cancers

Abstract

Abstract Recent whole-exome sequencing studies have found that somatic mutations frequently occur in splicing factors across multiple cancer types, supporting the need to systematically and globally characterize splicing alterations across human cancers. Somatic alterations that affect RNA processing of cancer genes may be caused by multiple mechanisms, including mutations in splicing factors, mutations in cis-acting splice sites and other regulatory sequences, alterations in methylation, or alterations in chromatin structure. For a global look at somatic RNA splicing alterations, we are applying the Cancer Outlier Profile Analysis (COPA) approach on ~7,000 cancer transcriptomes from 12 tumor types in The Cancer Genome Atlas (TCGA) and investigating the underlying somatic mutations that cause these splicing alterations using matched whole-exome, whole-genome, and methylation data from these samples. To identify and quantify alternative splicing in RNA-Seq data, including unannotated splicing events, we have further developed a computational pipeline called JuncBASE. To distinguish between cancer-specific splicing alterations and normal transcriptome variation, we are utilizing ~700 RNA-Seq libraries from healthy individuals from the Genotype-Tissue Expression (GTEx) project. COPA analysis of outlier splicing events in lung adenocarcinomas and glioblastomas successfully identified known altered splicing events in MET and EGFR, respectively, that are caused by DNA level somatic mutations. The genomic mechanisms for novel somatic splicing events in known cancer genes such as FGFR3, as well as genes previously uncharacterized in cancer genomes, are currently being investigated. To identify splicing events that may be novel somatic driver alterations, these events have been profiled using RNA-Seq data from the Cancer Cell Line Encyclopedia and are being used as biomarkers to identify genetic vulnerabilities in high-throughput shRNA screens. This work will have a significant impact on the identification of somatic splicing events that contribute to cancer pathogenesis. Citation Format: Angela N. Brooks, Yawei Ge, Kevin Chau, Samuel S. Freeman, Gordon Saksena, Chandra Sekhar Pedamallu, Matthew Meyerson. Identification of somatic RNA splicing alterations in human cancers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-21.