Abstract
SummaryWhole-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
Highlights
English physicians of the 18th century are credited with linking environmental exposures to cancer
Mechanisms underpinning how environmental carcinogens cause cancer are not fully understood, many cause DNA damage that results in mutations, as demonstrated experimentally in reporter genes and cancer-related genes (e.g., RAS and TP53) (DeMarini et al, 2001; Giglia-Mari and Sarasin, 2003; Pfeifer, 2000; Zhivagui et al, 2017)
Lung tumors from smokers harbor C > A/G > T transversion mutations in TP53 codons 157, 158, 245, 248, and 273 (Pfeifer, 2000). Guanines at these codons were preferentially adducted and mutated in cells treated with benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a reactive metabolite of the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BaP) from tobacco-smoke in human (Denissenko et al, 1996) and mouse embryo fibroblast (MEF) models (Kucab et al, 2015)
Summary
English physicians of the 18th century are credited with linking environmental exposures to cancer. Specific patterns associated with exposure to particular carcinogens have been identified in TP53 in human cancers too (Hollstein et al, 1991; Olivier et al, 2010), revealing that codon position, sequence context, and strand bias can be tumor-type- and carcinogenspecific. G > T transversions induced in vitro and those in lung cancers exhibit a strong transcriptional strand bias. This is believed to reflect transcription-coupled nucleotide excision repair (TC-NER) of bulky adducts formed by tobacco carcinogens (Hainaut and Pfeifer, 2001)
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