A compendium of mutational signatures of environmental and chemotherapeutic 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 of human induced pluripotent stem cells (iPSCs) following exposure to known or suspected environmental carcinogens. 79 agents were tested at concentrations that produced measurable cytotoxicity; 41 yielded characteristic substitution mutational signatures. Some exhibited similarity with 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 in iPSCs. Primary adducts induced by environmental carcinogens can be resolved by disparate repair/replicative pathways, resulting in an assortment of signature outcomes even for a single mutagen. 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.