The mutational landscapes of genetic and chemical models of Kras-driven lung cancer

Peter M.K. Westcott, Kyle D. Halliwill, Minh D. To, Mamunur Rashid, Alistair G. Rust, Thomas M. Keane, Reyno Delrosario, Kuang-Yu Jen, Kay E. Gurley, Christopher J. Kemp, Erik Fredlund, David A. Quigley, David J. Adams, Allan Balmain

Research output: Contribution to journalArticle

122 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)489-492
Number of pages4
JournalNature
Volume517
Issue number7535
DOIs
StatePublished - Jan 22 2015
Externally publishedYes

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Chemical Models
Genetic Models
Lung Neoplasms
Neoplasms
Carcinogens
Mutation
Exome
Urethane
Non-Small Cell Lung Carcinoma
Nucleotides
Aneuploidy
Human Genome

ASJC Scopus subject areas

  • General

Cite this

Westcott, P. M. K., Halliwill, K. D., To, M. D., Rashid, M., Rust, A. G., Keane, T. M., ... Balmain, A. (2015). The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature, 517(7535), 489-492. https://doi.org/10.1038/nature13898

The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. / Westcott, Peter M.K.; Halliwill, Kyle D.; To, Minh D.; Rashid, Mamunur; Rust, Alistair G.; Keane, Thomas M.; Delrosario, Reyno; Jen, Kuang-Yu; Gurley, Kay E.; Kemp, Christopher J.; Fredlund, Erik; Quigley, David A.; Adams, David J.; Balmain, Allan.

In: Nature, Vol. 517, No. 7535, 22.01.2015, p. 489-492.

Research output: Contribution to journalArticle

Westcott, PMK, Halliwill, KD, To, MD, Rashid, M, Rust, AG, Keane, TM, Delrosario, R, Jen, K-Y, Gurley, KE, Kemp, CJ, Fredlund, E, Quigley, DA, Adams, DJ & Balmain, A 2015, 'The mutational landscapes of genetic and chemical models of Kras-driven lung cancer', Nature, vol. 517, no. 7535, pp. 489-492. https://doi.org/10.1038/nature13898
Westcott PMK, Halliwill KD, To MD, Rashid M, Rust AG, Keane TM et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature. 2015 Jan 22;517(7535):489-492. https://doi.org/10.1038/nature13898
Westcott, Peter M.K. ; Halliwill, Kyle D. ; To, Minh D. ; Rashid, Mamunur ; Rust, Alistair G. ; Keane, Thomas M. ; Delrosario, Reyno ; Jen, Kuang-Yu ; Gurley, Kay E. ; Kemp, Christopher J. ; Fredlund, Erik ; Quigley, David A. ; Adams, David J. ; Balmain, Allan. / The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. In: Nature. 2015 ; Vol. 517, No. 7535. pp. 489-492.
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