We found that mutation frequency distributions for commonly mutated driver genes were conserved across multiple cancer mutation databases (Fig. 1a, b) and that innate mutation rates based on trinucleotide context significantly correlated with mutation frequencies for several genes ( Supplementary Information ).
The distribution of mutations in cancer is highly non-uniform. Mutations in oncogenes and tumour suppressors are enriched across cancers, and specific sites known as hotspots are more frequently mutated, leading to the hypothesis that hotspot mutations offer a selective advantage 1. A paradigmatic example is the tumour suppressor p53.
Extended Data Fig. 4 Fitness model predicts mutation frequencies in commonly mutated cancer driver genes. a, Degree to which models of varying complexity account for mutation distributions from TCGA and COSMIC, excluding TCGA samples, across 27 commonly mutated cancer driver genes.
Focusing on TP53, the most mutated gene in cancer 1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity.