Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

David G. McFadden, Katerina Politi, Arjun Bhutkar, Frances K. Chen, Xiaoling Song, Mono Pirun, Philip M. Santiago, Caroline Kim-Kiselak, James T. Platt, Emily Lee, Emily Hodges, Adam P. Rosebrock, Roderick T. Bronson, Nicholas D. Socci, Gregory J. Hannon, Tyler Jacks, Harold Varmus

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC protooncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Original languageEnglish (US)
Pages (from-to)E6409-E6417
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number42
DOIs
StatePublished - Oct 18 2016

Keywords

  • EGFR
  • Exome
  • GEMM
  • KRAS
  • MYC

ASJC Scopus subject areas

  • General

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    McFadden, D. G., Politi, K., Bhutkar, A., Chen, F. K., Song, X., Pirun, M., Santiago, P. M., Kim-Kiselak, C., Platt, J. T., Lee, E., Hodges, E., Rosebrock, A. P., Bronson, R. T., Socci, N. D., Hannon, G. J., Jacks, T., & Varmus, H. (2016). Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 113(42), E6409-E6417. https://doi.org/10.1073/pnas.1613601113