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 (KrasLA2). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the KrasLA2 model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the KrasLA2 model. By contrast, the KrasLA2 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 alterations1, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.
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European Nucleotide Archive
The raw .bam files have been deposited in the European Nucleotide Archive under accession number ERP001454.
This work was supported by National Cancer Institute (NCI) grants R01 CA111834, U01 CA84244, U01 CA141455 and UO1 CA176287 (to A.B.), and partly funded by the Bonnie Addario Foundation. P.M.K.W. was supported by the National Institutes of Health (NIH) training grant T32 GM007175 and a National Science Foundation GRFP award, and is currently supported by an NCI F31 NRSA award. K.D.H. was supported by the NIH training grant T32 GM007175, and is currently supported by an NCI F31 NRSA award. D.J.A. is supported by Cancer Research UK and the Wellcome Trust. We are appreciative of help and comments from our colleagues in refining this study and manuscript. We would also like to thank S. Busch for assistance with animal studies, and S. Green, T. Yuan and M. McMahon for providing the K493.1 cell line.