Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

Cell Reports

Juan Xu¹  Shiaw-Yih Lin²  Yongsheng Li²  Boranai Tychhon²  Daniel J. McGrail²  Nidhi Sahni²  Song Yi²  Xu Hua²  Dhanistha Sudhakar²  Limei Hu²  Xiaoqian Jiang³  Michael Ryan⁴  Michael Tyers⁵  Jasmin Coulombe-Huntington⁵  Rita Pancsa⁶  M. Madan Babu⁶ 

[1] College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150081, China;Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Division of Biomedical Informatics, University of California at San Diego, La Jolla, CA 92093, USA;In Silico Solutions, Falls Church, VA 22043, USA;Institute for Research in Immunology and Cancer, Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada;Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK;

关键词: Network biology;    alternative splicing;    gene regulation;    genotype-phenotype relationships;    DrAS-Net;    cancer;    somatic mutations;    systems biology;    computational biology;    bioinformatics;   

DOI  :  10.1016/j.celrep.2017.09.071

来源: DOAJ

【 摘 要 】

It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

【 授权许可】

Unknown