Abstract
Cancer growth is fueled by genomic alterations that confer selective advantage to somatic cells 1. A major goal of cancer biology is determining the relative importance of these alterations. Genomic tumor sequence surveys have frequently ranked the importance of genetic substitutions to cancer growth by P value or a false-discovery conversion thereof2,3. However, P values are thresholds for belief4, not metrics of effect5,6. Their frequent misuse as metrics of effect has often and ineffectively been vociferously decried 5,7–9, even in cases when the only attributable mistake was omission of effect sizes 10,11. Here, we draw upon an understanding of the development of cancer as an evolutionary process 12,13 to estimate the effect size of somatic variants. We estimate the effect size of all recurrent single nucleotide variants in 23 cancer types, ranking their relative importance within and between driver genes. Many of the variants with the highest effect size per tumor, such as EGFR L858R in lung adenocarcinoma and BRAF V600E in colon adenocarcinoma, are within genes deemed significantly mutated by existing whole-gene metrics. Quantifying the effect sizes of somatic mutations underlying cancer has immediate significance to the prioritization of clinical decision-making by tumor boards, selection and design of clinical trials, pharmacological targeting, and basic research prioritization.
