Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Abstract Comprehensive analyses of genome-wide mutation profiles has revealed that specific anti-cancer drugs, such as 5-fluorouracil (5-FU), are highly mutagenic to cancer cells and cultured cells. The systemic administration of these chemotherapies presents a potential genotoxic hazard to healthy tissues, however, the true mutational impact on normal cells of patients is not known. Here, we examined genome-wide somatic mutation patterns in healthy adult stem cells (ASCs) of the colon or the liver from 14 colorectal cancer patients that received first-line systemic chemotherapy and/or local radiotherapy. The platinum-based chemo-drug Oxaliplatin induced 500-1000 mutations in each colon ASC of all treated patients. The effects of 5-FU treatment were more variable between cells and patients, ranging from a complete absence of 5-FU mutagenesis to the accumulation of up to 500 mutations in individual colon ASCs. In contrast with the colon, normal ASCs from the liver escaped platinum and 5-FU mutagenesis after systemic treatment. Local radiation therapy resulted in the accumulation of 50-100 deletions between 5bp to 10kbp and structural rearrangements in colon ASCs. Thus, while 5-FU and platinum drugs are highly effective at killing cancer cells, their systemic use does also lead to a concomitant increase of the mutational burden in long-lived normal stem cells responsible for tissue renewal and thus pose a potential source for developing second cancers.