Abstract 3294: Functional annotation for alternative splicing to investigate disrupted splicing in cancer

Abstract

Abstract Alternative splicing (AS) plays a key role to confer human genome complexity. The advent of mRNA high-throughput sequencing facilitates to identify precise differential alternative splicing analysis. Massive result estimated from RNA-Seq should be sorted out whether AS has functional impact or not. Previous studies investigated protein domain or nonsense-mediated decay of AS event region. However other functional sites on exon inclusion region also exist. For example, miRNA binding site, and post-translational modification of AS site already are reported to assign functional impact. Therefore we developed ASpedia (http://combio.snu.ac.kr/aspedia/) to annotation functional impact of AS event. AS events of our database were generated from human genome hg19 ENSEMBL and Refseq. ASpedia provides a database, explore system, and AS browser to annotate functional impact evidence encompassing DNA, RNA, and protein. The user could query multiple AS events from differential AS analysis result. Currently our system supports a jar execution file to convert input query file from MISO or rMATS result. The variant of splicing factor (SF) disrupts normal splicing. It could be assumed that target genes of mutated SF could be transcribed to aberrant isoforms by changed splicing machinery. Therefore we investigated the comprehensive SF variant status from TCGA somatic mutation and copy number. SF3B1 (2% in BRCA) and U2AF1 (4% in AML, and 2% in LUAD) were shown to recurrent mutation including hotspot. ELAVL2 known dispensable splicing factor to brain tissue were highly recurrent in deletion (18% in GBM). In order to examine aberrant AS events caused SF variants, we estimated exon-inclusion proportion Percent-Spliced-In (PSI) values for identifiable AS events using TCGA RNA-Seq dataset. Using differentially AS event analysis, we identified AS events that were significantly differentially spliced in the presence of a U2AF S34F/Y mutation (119 in AML). And we purposed to finding In order to investigate functional site, the differentially spliced AS events were additionally annotated using ASpedia. Finally we identified the landscape of that AS events were altered by SF variants, and we proved that a part of the events was involved in cancer-associated functions. Citation Format: Daejin Hyung, Jihyun Kim, Soo Young Cho, Charny Park. Functional annotation for alternative splicing to investigate disrupted splicing in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3294.