title: The genome as a record of environmental exposure.
abstract: Whole genome sequencing of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. Experimental investigations of the mutations and mutation spectra induced by environmental mutagens have traditionally focused on single genes. With the advent of faster cheaper sequencing platforms, it is now possible to assess mutation spectra in experimental models across the whole genome. As a proof of principle, we have examined the whole genome mutation profiles of mouse embryo fibroblasts immortalised following exposure to benzo[a]pyrene (BaP), ultraviolet light (UV) and aristolochic acid (AA). The results reveal that each mutagen induces a characteristic mutation signature: predominantly G→T mutations for BaP, C→T and CC→TT for UV and A→T for AA. The data are not only consistent with existing knowledge but also provide additional information at higher levels of genomic organisation. The approach holds promise for identifying agents responsible for mutations in human tumours and for shedding light on the aetiology of human cancer.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, London SE1 9NH, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Kucab
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
authors.forename: Sandro
authors.initials: S
authors.lastname: Morganella
authors.forename: Dominik
authors.initials: D
authors.lastname: Glodzik
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, London SE1 9NH, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: German Cancer Research Center (Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and.
authors.forename: Annette
authors.initials: A
authors.lastname: Weninger
authors.affiliation: German Cancer Research Center (Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and University of Leeds, Faculty of Medicine and Health, Leeds LS2 9JT, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, London SE1 9NH, UK, david.phillips@kcl.ac.uk.
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D004261:DNA Replication; D004781:Environmental Exposure / Q000009:adverse effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016678:Genome; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D016296:Mutagenesis; D009153:Mutagens / Q000009:adverse effects; D009154:Mutation; D009369:Neoplasms / Q000209:etiology; D014158:Transcription, Genetic
chemical_list: D009153:Mutagens