Comprehensive Characterization of Cancer Driver Genes and Mutations

Abstract

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

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Affiliated Institutions

• University of Miami US
• Massachusetts General Hospital US
• Discovery Institute US
• Harvard University US
• University of California, Santa Cruz US
• Université Libre de Bruxelles BE
• Sanford Burnham Prebys Medical Discovery Institute US
• Institute for Research in Biomedicine ES
• James S. McDonnell Foundation US
• University of Cambridge GB
• Institució Catalana de Recerca i Estudis Avançats ES
• Dana-Farber Cancer Institute US
• Barcelona Supercomputing Center ES
• The University of Texas MD Anderson Cancer Center US
• Johns Hopkins University US
• Genome Institute of Singapore SG
• Cornell University US
• Universitat Politècnica de Catalunya ES
• Broad Institute US
• Washington University in St. Louis US
• Memorial Sloan Kettering Cancer Center US
• Molecular Oncology (United States) US
• Weill Cornell Medicine US
• Baylor College of Medicine US

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