Imprints of tumor mutation burden on chromosomes and relation to cancer risk in humans: A pan-cancer analysis

Cancers, resulting in uncontrolled cell proliferation, are driven by accumulation of somatic mutations. Genome-wide sequencing has produced a catalogue of millions of somatic mutations, which contain the evolutionary history of the cancers. However, the connection between the mutation accumulation and disease development and risks is poorly understood. Here, we analyzed more than 1,200,000 mutations from 5,000 cancer patients with whole-exome sequencing, and discovered two novel signatures for 16 cancer types in The Cancer Genome Atlas (TCGA) database. A strong correlation between Tumor Mutation Burden (TMB) and the Patient Age at Diagnosis (PAD) is observed for cancers with low TMB (mean value less than 3 mutations per million base pairs) but is absent in cancers with high TMB. We also validate this finding using whole-genome sequencing data from more than 2,000 patients for 24 cancer types. Surprisingly, the differences in cancer risk between the sexes are also mainly driven by the disparity in mutation burden. The TMB variations, imprinted at the chromosome level, also reflect accumulation of mutation clusters within small chromosome segments in high TMB cancers. By analyzing the characteristics of mutations based on multi-region sequencing, we found that a combination of TMB and intratumor heterogeneity could a potential biomarker for predicting the patient survival and response to treatment.