Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer
Yongsheng Li,
Nidhi Sahni,
Rita Pancsa,
Daniel J. McGrail,
Juan Xu,
Xu Hua,
Jasmin Coulombe-Huntington,
Michael Ryan,
Boranai Tychhon,
Dhanistha Sudhakar,
Limei Hu,
Michael Tyers,
Xiaoqian Jiang,
Shiaw-Yih Lin,
M. Madan Babu,
Song Yi
Affiliations
Yongsheng Li
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Nidhi Sahni
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Rita Pancsa
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
Daniel J. McGrail
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Juan Xu
College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150081, China
Xu Hua
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jasmin Coulombe-Huntington
Institute for Research in Immunology and Cancer, Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada
Michael Ryan
In Silico Solutions, Falls Church, VA 22043, USA
Boranai Tychhon
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Dhanistha Sudhakar
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Limei Hu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Michael Tyers
Institute for Research in Immunology and Cancer, Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada
Xiaoqian Jiang
Division of Biomedical Informatics, University of California at San Diego, La Jolla, CA 92093, USA
Shiaw-Yih Lin
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
M. Madan Babu
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
Song Yi
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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.
