Journal
CELL REPORTS
Volume 21, Issue 3, Pages 798-812Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.071
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Funding
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR160021]
- University of Texas System Rising STARs award
- NIH/NCI award [P30CA016672]
- University Center Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center
- Medical Research Council of the UK [MC_U105185859]
- EMBO Long Term Fellowship [ALTF 702-2015]
- Partnership for Careers in Cancer Science and Medicine at The University of Texas MD Anderson Cancer Center
- Canadian Institutes of Health Research (CIHR)
- CIHR [MOP-126129]
- Canadian Cancer Society Research Institute [703906]
- NIH [R01RR024031]
- Ministere de l'enseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec
- Medical Research Council [MC_U105185859] Funding Source: researchfish
- MRC [MC_U105185859] Funding Source: UKRI
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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.
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