LAUSR

Abstract Mutational processes in tumors create distinctive patterns of mutations, composed of neutral “passenger” mutations and oncogenic drivers that have quantifiable effects on the proliferation and survival of cancer cell lineages. Increases in proliferation and survival are mediated by natural selection, which can be quantified by comparing the frequency at which we detect substitutions to the frequency at which we expect to detect substitutions assuming neutrality. Most of the variants detectable with whole-exome sequencing in tumors are neutral or nearly neutral in effect, and thus the processes generating the majority of mutations may not be the primary sources of the tumorigenic mutations. Across 24 cancer types, we identify the contributions of mutational processes to each oncogenic variant and quantify the degree to which each process contributes to tumorigenesis. We demonstrate that the origination of variants driving melanomas and lung cancers is predominantly attributable to the preventable, exogenous mutational processes associated with ultraviolet light and tobacco exposure, respectively, whereas the origination of selected variants in gliomas and prostate adenocarcinomas is largely attributable to endogenous processes associated with aging. Preventable mutations associated with pathogen exposure and apolipoprotein B mRNA-editing enzyme activity account for a large proportion of the cancer effect within head-and-neck, bladder, cervical, and breast cancers. These attributions complement epidemiological approaches—revealing the burden of cancer driven by single-nucleotide variants caused by either endogenous or exogenous, nonpreventable, or preventable processes, and crucially inform public health strategies.