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

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

doi:10.1371/journal.pone.0087361

Angela N Brooks, Mara Rosenberg + Show 12 more

Open Access

https://doi.org/10.1371/journal.pone.0087361

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Abstract

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.

Highlights

Recent whole-exome sequencing studies have identified recurrent somatic mutations in splicing factors in myelodysplastic syndromes [1], chronic lymphocytic leukemia [2], acute myeloid leukemia [3], breast cancer [4], lung adenocarcinoma [5], and uveal melanoma [6]
Somatic mutations in U2AF1 across 12 cancer types To look at transcriptome changes associated with U2AF1 mutations in different cancer types, we used The Cancer Genome Atlas (TCGA) data that provide both somatic mutations at the DNA level and high-throughput sequencing of mRNA (RNA-Seq) in the same individual specimens across multiple cancer types
U2AF1 S34F mutations were found in eight lung adenocarcinomas (4%), four acute myeloid leukemias (AML) samples (2%), two endometrial carcinomas (1%), and one bladder cancer sample (1%)

Summary

Introduction

Recent whole-exome sequencing studies have identified recurrent somatic mutations in splicing factors in myelodysplastic syndromes [1], chronic lymphocytic leukemia [2], acute myeloid leukemia [3], breast cancer [4], lung adenocarcinoma [5], and uveal melanoma [6]. Many of these mutated splicing factors are branch point or 39 splice site recognition factors (e.g., SF3B1 and U2AF1) and are involved in regulating intron removal from premRNA. To further elucidate core effects of U2AF1 mutations on cancer biology, we aimed to identify common transcriptome alterations associated with U2AF1 mutations in distinct cancer types

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