The mutational footprints of cancer therapies

Some cancer therapies damage DNA and cause mutations both in cancer and healthy cells of the patient. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicities and secondary neoplasms. Currently we ignore the mutation burden caused by different cancer treatments. Here we identify mutational signatures, or footprints of six widely-used anti-cancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs, and a novel signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precisely assessing the mutational risk of different cancer therapies to understand their long-term side effects.