Abstract 3150: Characterizing the effects of somatic mutations in splice factors on the transcriptome.

Abstract

Abstract Recent studies have identified recurrent somatic mutations in splice factors, including SF3B1 and U2AF1, in myelodysplastic syndromes, chronic lymphocytic leukemias, breast cancer, and lung adenocarcinoma. In one study, 91 tumor and matched normal whole-exomes were sequenced from patients with CLL and the second most frequently mutated gene was SF3B1. Analysis of 187 whole-exomes in lung adenocarcinoma and matched normals revealed recurrent somatic mutations in the splice factor U2AF1 in 3% of cases. In addition to U2AF1 mutations, recurrent truncating mutations were observed in a putative splice factor, RBM10, in 4% of lung adenocarcinomas. The recurrence of somatic mutations in splice factors in multiple tumor types suggests that alterations in RNA splicing may play an important role in tumorigenesis. Although these mutations have been identified in cancer genomes, the effect on the cancer transcriptome has yet to be fully explored; therefore, we do not understand how mutations in splice factors can contribute to tumorigenesis. We hypothesize that somatic mutations in splice factors cause alterations in mRNA splicing of important cancer genes. We are using a computational tool called JuncBASE to identify alternative splicing in tumor transcriptomes from RNA-Seq data. We are then associating somatic mutations in splice factors, found from whole-exome sequencing, with splicing signatures identified through RNA-Seq. Preliminary results on the identification of splice events associated with SF3B1 mutations in CLL reveal novel isoforms of multiple genes specifically expressed in SF3B1 mutant samples. Additionally, we examined the effects of SF3B1, U2AF1, and RBM10 mutations on tumor transcriptomes using RNA-Seq data from The Cancer Genome Atlas. Citation Format: Angela N. Brooks, Youzhong Wan, Peter Choi, Rui Jing, David S. DeLuca, Carrie Sougnez, Juliann Chmielecki, Marcin Imielinski, Gad Getz, Catherine J. Wu, Matthew Meyerson. Characterizing the effects of somatic mutations in splice factors on the transcriptome. [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 3150. doi:10.1158/1538-7445.AM2013-3150