A Compendium of Mutational Signatures of Environmental Agents

Jill E Kucab; Xueqing Zou; Sandro Morganella; Madeleine Joel; A Scott Nanda; Eszter Nagy; Celine Gomez; Andrea Degasperi; Rebecca Harris; Stephen P Jackson; Volker M Arlt; David H Phillips; Serena Nik-Zainal

doi:10.1016/j.cell.2019.03.001

A Compendium of Mutational Signatures of Environmental Agents

Cell. 2019 May 2;177(4):821-836.e16. doi: 10.1016/j.cell.2019.03.001. Epub 2019 Apr 11.

Authors

Affiliations

¹ Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King's College London, 150 Stamford Street, London SE1 9NH, UK.
² Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
³ Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁴ Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK.
⁵ Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁶ The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
⁷ Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King's College London, 150 Stamford Street, London SE1 9NH, UK. Electronic address: david.phillips@kcl.ac.uk.
⁸ Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address: snz@mrc-cu.cam.ac.uk.

Abstract

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.

Keywords: DNA damage; Mutational signatures; carcinogens; environmental mutagens; mutagenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogens, Environmental / adverse effects
Carcinogens, Environmental / classification*
DNA Damage / genetics
DNA Mutational Analysis / methods
DNA Repair / genetics
DNA Replication
Genetic Profile
Genome, Human / genetics
Humans
INDEL Mutation / genetics
Mutagenesis
Mutation / genetics
Neoplasms / genetics*
Pluripotent Stem Cells / metabolism
Whole Genome Sequencing / methods

Substances

Carcinogens, Environmental

Abstract

Publication types

MeSH terms

Substances

Grants and funding