Journal Article

A Pan-Cancer Analysis of Transcriptome Changes Associated with Somatic Mutations in U2AF1 Reveals Commonly Altered Splicing Events

Pedamallu, Chandra Sekhar, Brooks, Angela N., Sivachenko, Andrey, Rosenberg, Mara, Saksena, Gordon, Lawrence, Michael S., DeLuca, David S., Meyerson, Matthew, Choi, Peter S., de Waal, Luc, Sharifnia, Tanaz, Imielinski, Marcin, Getz, Gad, Chmielecki, Juliann

2014

Overview

Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35) have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA). Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML), in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute Disease / Adenocarcinoma / Adenocarcinoma - genetics / Amino acids / Analysis / Bioinformatics / Biology / Cancer / Cancer genetics / Cell adhesion & migration / Cell cycle / Deoxyribonucleic acid / DNA / DNA sequencing / Gene expression / Gene Expression Regulation, Neoplastic - genetics / Gene sequencing / Genes / Genetic aspects / Genomes / Genomics / HEK293 Cells / HeLa Cells / Humans / Leukemia / Leukemia, Myeloid - genetics / Logos / Lung cancer / Lung Neoplasms - genetics / Lungs / Medicine / Mutation / Neoplasms - genetics / Nuclear Proteins - genetics / Oncology / Reverse Transcriptase Polymerase Chain Reaction / Ribonucleic acid / Ribonucleoproteins - genetics / RNA / RNA sequencing / RNA Splice Sites - genetics / RNA Splicing - genetics / Splicing Factor U2AF / Splicing factors / Statistical analysis / T cells / Transcriptome - genetics / Trinucleotide repeats