Tumor mutation burden signatures and relation to cancer risk in humans: A pan-cancer analysis

Cancers, resulting in uncontrolled cell proliferation, are driven by accumulation of so- matic mutations. Whole-genome sequencing has produced a catalogue of millions of somatic mutations, which contain the evolutionary history of the cancers. However, the connection between the extent and rate of mutation accumulation and disease development and risks are poorly understood. We analyzed data from 5,000 cancer patients with more than 1,200,000 mutations for 16 cancer types using The Cancer Genome Atlas (TCGA) database to unearth markers of tumor evolution. A strong correlation between Tumor Mutation Burden (TMB) and the Patient Age at Diagno- sis (PAD) for cancers with low TMB (mean value less than 3 mutations per million base pairs) is absent in cancers with high TMB. The finding, demarcating cancers according to the TMB, resolves controversies relating the dynamics of mutation ac- cumulation and disease risks for different cancers. We also find that the differences in cancer risk between the sexes are mainly driven by the disparity in mutation burden. A simple model, explaining these results, also show that immunotherapy could work well for elderly melanoma patients.