The mutational landscapes of genetic and chemical models of Kras-driven lung cancer
Open Access
- 2 November 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 517 (7535), 489-492
- https://doi.org/10.1038/nature13898
Abstract
Whole-exome sequencing is used to compare the mutational landscape of adenomas from three mouse models of non-small-cell lung cancer, induced either by exposure to carcinogens or by genetic mutation of Kras; the results reveal that the two types of tumour have different mutational profiles and adopt different routes to tumour development. Allan Balmain and colleagues use whole-exome sequencing to compare the mutational landscape of adenomas from three mouse models of non-small cell lung cancer, induced by exposure to the carcinogens methyl-nitrosourea (MNU) and urethane, or by genetic activation of Kras (KrasLA2). Although the MNU-induced and KrasLA2 tumours carried the same initiating Kras mutation, MNU tumours also carry numerous non-synonymous point mutations. At the same time, KrasLA2 tumours carried numerous copy number alterations. This suggests that carcinogen-induced and genetically engineered models adopt different routes to tumour development. The results argue for a major role of germline Kras status in mutation selection during initiation. Collectively, these data demonstrate the utility of carcinogen models for understanding the complex mutation spectra seen in human cancers. 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.Keywords
This publication has 42 references indexed in Scilit:
- Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesisOncogene, 2012
- The Origin and Evolution of Mutations in Acute Myeloid LeukemiaCell, 2012
- A Comprehensive Survey of Ras Mutations in CancerCancer Research, 2012
- Reduced expression of MTUS1 mRNA is correlated with poor prognosis in bladder cancerOncology Letters, 2012
- COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in CancerNucleic Acids Research, 2010
- Down-regulation of MTUS1 in human colon tumors.Oncology Reports, 2009
- The cancer genomeNature, 2009
- Mutation analysis of the 8p22 candidate tumor suppressor gene ATIP/MTUS1 in hepatocellular carcinomaMolecular and Cellular Endocrinology, 2006
- Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasGenes & Development, 2001
- Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinaseProceedings of the National Academy of Sciences of the United States of America, 1997