TY - JOUR T1 - CHASMplus reveals the scope of somatic missense mutations driving human cancers JF - bioRxiv DO - 10.1101/313296 SP - 313296 AU - Collin Tokheim AU - Rachel Karchin Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/24/313296.abstract N2 - Large-scale cancer sequencing studies of patient cohorts have statistically implicated many cancer driver genes, with a long-tail of infrequently mutated genes. Here we present CHASMplus, a computational method to predict driver missense mutations, which is uniquely powered to identify rare driver mutations within the long-tail. We show that it substantially outperforms comparable methods across a wide variety of benchmark sets. Applied to 8,657 samples across 32 cancer types, CHASMplus identifies over 4,000 unique driver mutations in 240 genes, further distinguished by their specific cancer types. Our results support a prominent emerging role for rare driver mutations, with substantial variability in the frequency spectrum of drivers across cancer types. The trajectory of driver discovery may already be effectively saturated for certain cancer types, a finding with policy implications for future sequencing. As a resource to handle newly observed rare driver mutations, we systematically score every possible missense mutation across the genome.Significance With the ever-growing pace of DNA sequencing of human tumors, the total number of detected mutations in cancer continues to accelerate. However, only a few mutations in each tumor may actually “drive” the growth of cancer, some of which can have value for diagnostic, prognostic, or therapeutic purposes. Based on a new rigorous statistical analysis of The Cancer Genome Atlas (TCGA), we find a prominent emerging role for rare missense mutations predicted to be “drivers” of cancer, which may have potential implications for genome-driven precision oncology, since rare driver mutations that are putatively actionable could be newly observed in a patient, thus, requiring personalized modeling and assessment. To extend beyond the TCGA, we provide a systematic resource to assess such newly observed missense mutations as cancer drivers. Lastly, we assess the driver landscape of human cancers and find that discovery for some cancer types are already approaching saturation. ER -