Brooks Angela N, Choi Peter S, de Waal Luc, Sharifnia Tanaz, Imielinski Marcin, Saksena Gordon, Pedamallu Chandra Sekhar, Sivachenko Andrey, Rosenberg Mara, Chmielecki Juliann, Lawrence Michael S, DeLuca David S, Getz Gad, Meyerson Matthew
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.
Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS One. 2014 Jan 31;9(1):e87361. doi: 10.1371/journal.pone.0087361. eCollection 2014.
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.
尽管在多种癌症类型中已发现剪接因子U2AF1（也称为U2AF35）存在复发性体细胞突变，但这些突变对癌症转录组的影响尚未完全阐明。在此，我们使用来自癌症基因组图谱（TCGA）的DNA和RNA测序数据，确定了不同癌症中与U2AF1突变相关的剪接改变。利用来自182例肺腺癌和167例急性髓性白血病（AML）的RNA测序数据（其中3%-4%的病例中U2AF1发生体细胞突变），我们分别确定了131种和369种与U2AF1突变显著相关的剪接改变。其中，30种剪接改变在肺腺癌和AML中均具有统计学意义，包括癌症基因普查中的三个基因，即CTNNB1、CHCHD7和PICALM。在HeLa细胞和293T细胞中表达U2AF1 S34F的细胞系实验进一步支持了这些剪接改变事件是由U2AF1突变引起的。与U2AF1在3'剪接位点识别中的功能一致，我们发现S34F/Y突变导致对CAG而非UAG 3'剪接位点序列的偏好。本报告证明了U2AF1突变在不同癌细胞类型中对剪接具有一致的影响。
