A compendium of mutational signatures of environmental agents Kucab et al.

Whole-genome-sequencing (WGS) of human tumours has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. 41 yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumours. Additionally, 6 agents produced double-substitution signatures and 8 produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair/replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally-induced mutational signatures permits further exploration of roles of environmental agents in cancer aetiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.