A Compendium of Mutational Signatures of Environmental Agents

Summary

Whole-genome-sequencing (WGS) of human tumors 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. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight 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 and/or 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 etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents.

Video Abstract

Graphical Abstract

Highlights

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  41 of 79 environmental agents yielded substitution signatures

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  6 agents produced double-substitution signatures and 8 produced indel signatures

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  Several signatures match or exhibit similarity with signatures found in human tumors

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  Topographical mutational asymmetries reveal mechanistic insights

Abstract

The effects of a range of environmental mutagens in terms of the kinds of mutations they induce and how these are repaired by the cell is presented in the form of a resource.