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    CHASMplus Reveals the Scope of Somatic Missense Mutations Driving Human Cancers
    Graphical Abstract
    d CHASMplus identifies driver missense mutations in a cancer-type-specific manner
    d Rare driver mutations are common in cancer when considered as a group
    d In some cancers, further sequencing will yield insight into rare driver mutations
    d Comprehensive resource of driver propensity for all possible missense mutations 
    Collin Tokheim, Rachel Karchin
    [email protected]
    In Brief
    Tokheim et al. introduce a computational approach to accurately separate driver from passenger mutations in cancer. Their analysis revealed that most driver mutations occur only in a few patients, presenting a challenge for precision medicine, and several cancer types will benefit from additional sequencing to identify these rare driver mutations.
    Cell Systems Article
    CHASMplus Reveals the Scope of Somatic Missense Mutations Driving Human Cancers
    Collin Tokheim1,2 and Rachel Karchin1,2,3,4,* 1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA 2Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA 3Department of Oncology, Johns Hopkins University, Baltimore, MD 21204, USA 4Lead Contact *Correspondence: [email protected]
    Large-scale cancer sequencing studies of patient co-horts have statistically implicated many genes driving cancer growth and progression, and their identifica-tion has yielded substantial translational impact. However, a remaining challenge is to increase the res-olution of driver prediction from the level of genes to mutations because mutation-level predictions are more closely aligned with the goal of precision cancer medicine. Here, we present CHASMplus, a computa-tional method that is uniquely capable of identifying driver missense mutations, including those specific to a cancer type, as evidenced by significantly supe-rior performance on diverse benchmarks. Applied to 8,657 tumor samples across 32 cancer types in The Cancer Genome Atlas (TCGA), CHASMplus identifies over 4,000 unique driver missense mutations in 240 genes, supporting a prominent role for rare driver mu-tations. We show which TCGA cancer types are likely to yield discovery of new driver missense mutations by additional sequencing, which has important impli-cations for public policy.