Anti-Cancer Therapies Induce Mutations in Adult Stem Cells in a Tissue-Specific Manner

ABSTRACT: Systematic analyses of genome-wide mutation profiles of cancer cells and cultured cells have recently shown that some anticancer treatments are highly mutagenic. Since most treatments are typically given systemically, any healthy cell in the body exposed to the treatment drug may also accumulate therapy induced mutations. However, quantitative insights of treatment-induced mutations in normal tissues remain elusive. Here, we determine genome-wide mutation patterns in healthy adult stem cells (ASCs) of either the colon or the liver of 14 colorectal cancer patients after treatment with mutagenic anti-cancer therapies. Capecitabine/Oxaliplatin (CAPOX) induces 500-1000 mutations with a platinum-induced footprint in each colon adult stem cell. In contrast, capecitabine, which is metabolized to 5-fluorouracil (5-FU), effects strongly vary between and within patients with some colon ASCs accumulating up to 500 mutations from 5-FU, while most other colon ASCs show a complete absence of 5-FU mutagenesis. Finally, our results show that local radiation therapy induces deletions of >5bp - 10kbp as well as structural rearrangements including reciprocal and multi-breakpoint variants in colon ASCs. Surprisingly and unlike colon ASCs, healthy liver ASCs of systemically treated colon cancer patients show no therapy-related mutations. Taken together, our results reveal that colon ASCs are particularly vulnerable to platinum-based therapies and to a lesser extent to treatments with 5-FU and may explain why platinum-based therapies, and not 5-FU, are associated with secondary malignancies. Consequently, while anticancer treatments are efficient in killing cancer cells, they increase the mutation burden in healthy cells explaining why treatment is an important risk factor for second cancers, but their mutational impact on healthy cells markedly differs between chemodrug and between tissue.

PROVIDER: EGAS00001006042 | EGA |

REPOSITORIES: EGA