Abstract
Whole-genome sequencing of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 whole-genome sequences of human-induced pluripotent stem cells (iPSCs) following exposure to known or suspected environmental carcinogens. 79 agents were tested with or without metabolic activation at concentrations that produced measurable cytotoxicity; 41 yielded characteristic substitution mutational signatures that, in some cases, exhibit similarity with signatures found in human tumors. Additionally, 6 agents produced double-substitution signatures and 8 also produced indel signatures. Investigating mutation distribution asymmetries across genome topography reveals 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 etiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.
Citation Format: Serena Nik-Zainal. A compendium of mutational signatures due to environmental exposures [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA19.
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