The genome as a record of environmental exposure

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.

[1]  H. Green,et al.  QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES , 1963, The Journal of cell biology.

[2]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[3]  B. Arcangioli,et al.  Fission yeast switches mating type by a replication–recombination coupled process , 2000, The EMBO journal.

[4]  David M. Gilbert,et al.  Making Sense of Eukaryotic DNA Replication Origins , 2001, Science.

[5]  M. Hollstein,et al.  Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool , 2001, Oncogene.

[6]  J. Dalgaard,et al.  RNase-sensitive DNA modification(s) initiates S. pombe mating-type switching. , 2004, Genes & development.

[7]  M. Hollstein,et al.  Human tumor p53 mutations are selected for in mouse embryonic fibroblasts harboring a humanized p53 gene. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Hollstein,et al.  p53 mutations in benzo(a)pyrene-exposed human p53 knock-in murine fibroblasts correlate with p53 mutations in human lung tumors. , 2005, Cancer research.

[9]  N. Rhind,et al.  DNA replication timing: random thoughts about origin firing , 2006, Nature Cell Biology.

[10]  M. Hollstein,et al.  Mutagenesis of human p53 tumor suppressor gene sequences in embryonic fibroblasts of genetically-engineered mice. , 2007, Genetic engineering.

[11]  E. Birney,et al.  Velvet: algorithms for de novo short read assembly using de Bruijn graphs. , 2008, Genome research.

[12]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[13]  M. Hollstein,et al.  Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72. , 2007, Oncogene.

[14]  M. Stratton,et al.  The cancer genome , 2009, Nature.

[15]  Z. Ning,et al.  Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of GC-biased genomes , 2009, Nature Methods.

[16]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[17]  M. Hollstein,et al.  TP53 mutation signature supports involvement of aristolochic acid in the aetiology of endemic nephropathy‐associated tumours , 2009, International journal of cancer.

[18]  Kai Ye,et al.  Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads , 2009, Bioinform..

[19]  J. Kucab,et al.  Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock‐in (Hupki) mouse model , 2010, The FEBS journal.

[20]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[21]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[22]  Magali Olivier,et al.  TP53 mutations in human cancers: origins, consequences, and clinical use. , 2010, Cold Spring Harbor perspectives in biology.

[23]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[24]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[25]  A. Børresen-Dale,et al.  Mutational Processes Molding the Genomes of 21 Breast Cancers , 2012, Cell.

[26]  K. Kinzler,et al.  Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing , 2013, Science Translational Medicine.

[27]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[28]  P. A. Futreal,et al.  Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool , 2013, Science Translational Medicine.

[29]  M. Stratton,et al.  Deciphering Signatures of Mutational Processes Operative in Human Cancer , 2013, Cell reports.

[30]  Asif U. Tamuri,et al.  Genome sequencing of normal cells reveals developmental lineages and mutational processes , 2014, Nature.

[31]  X. Castells,et al.  Modelling mutational landscapes of human cancers in vitro , 2014, Scientific Reports.

[32]  Peter J. Campbell,et al.  C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency , 2014, Genome research.

[33]  A. Izzotti,et al.  Molecular Fingerprints of Environmental Carcinogens in Human Cancer , 2015, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews.

[34]  Paul Nurse,et al.  The spatial and temporal organization of origin firing during the S-phase of fission yeast , 2015, Genome research.