Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer

The clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. SIM employs error-prone polymerases resulting in mutations concentrated around DNA double-strand breaks with an abundance that decays with genomic distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1,950 tumors and non-inherited mutations from 129 normal samples. We introduce statistical methods to identify mutational clusters and quantify their distribution patterns. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. We also found that clusters of mutations colocalize more prevalently in normal samples than in cancer, suggesting loss of regulation leading to increased randomness in the mutational process during carcinogenesis.