William D. Dupont

PURPOSE Long-standing clinical predictors of cancer survival have included histopathologic type, stage, and grade. We hypothesized that the principal categories of tumor somatic mutations might also portend survival. We investigated this hypothesis using the Pan-Cancer Atlas, encompassing clinical, genomic, and outcome data of 10,652 patients and 32 cancer types. METHODS We evaluated the prognostic capability of cancer type, stage, grade and the burden of each major mutation category on overall and disease-specific survival. Mutation categories included short substitution and insertion-deletion mutations (SMs), copy number alterations (CNAs), and gene fusions. RESULTS SM count and CNA fraction proved to be strong independent predictors of survival (joint P = 5.3e−95) that remained highly significant when adjusted for the traditional factors. Importantly, the relationship between mutation burden and survival proved to be nonlinear ( P = 9.5e−56); survival improved at both low- and high-burden extremes. In clinically predictive modeling, SM count together with CNA fraction meaningfully distinguished survival even among patients sharing a given cancer type, stage, or grade. CONCLUSION Burden of somatic mutation is a key index of survival of analogous clinical utility to these traditional factors.