title: The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.
abstract: Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Peter M K
authors.initials: PM
authors.lastname: Westcott
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Halliwill
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Minh D
authors.initials: MD
authors.lastname: To
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Mamunur
authors.initials: M
authors.lastname: Rashid
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keane
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Reyno
authors.initials: R
authors.lastname: Delrosario
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Gurley
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 21, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: 1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014520:Urethane / Q000633:toxicity
chemical_list: D002273:Carcinogens; D014520:Urethane; D008770:Methylnitrosourea; C495971:Hras protein, mouse; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)