A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events.
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.
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Angela N
AN
Brooks
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Peter S
PS
Choi
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Luc
L
de Waal
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Tanaz
T
Sharifnia
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Marcin
M
Imielinski
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Gordon
G
Saksena
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Chandra Sekhar
CS
Pedamallu
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Andrey
A
Sivachenko
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Mara
M
Rosenberg
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Juliann
J
Chmielecki
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Michael S
MS
Lawrence
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
David S
DS
DeLuca
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Gad
G
Getz
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America ; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.
Matthew
M
Meyerson
D000208:Acute Disease; D000230:Adenocarcinoma / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics*; D000072668:Splicing Factor U2AF; D059467:Transcriptome / Q000235:genetics*
D009687:Nuclear Proteins; D022821:RNA Splice Sites; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human