Journal
CELL
Volume 177, Issue 4, Pages 821-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.03.001
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Funding
- Wellcome Trust Strategic Award [101126/B/13/Z]
- University of Cambridge
- Wellcome Intermediate Clinical Fellowship [WT100183MA]
- CRUK Advanced Clinician Scientist Award [C60100/A23916]
- King's College London
- Wellcome Trust [101126/B/13/Z, WT100183MA, C60100/A23916]
- Cancer Research UK [C313/A14329]
- CRUK Pioneer Award
- Wellcome Trust [101126/B/13/Z] Funding Source: Wellcome Trust
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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 fur ration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents.
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