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

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. (October 2016) Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc Natl Acad Sci U S A, 113 (42). E6409-E6417. ISSN 1091-6490 (Electronic)0027-8424 (Linking)

[img]
Preview
PDF (Paper)
Hannon PNAS 2016.pdf - Published Version

Download (924Kb) | Preview
URL: https://www.ncbi.nlm.nih.gov/pubmed/27702896
DOI: 10.1073/pnas.1613601113

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 proto-oncogene. 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.

Item Type: Paper
Uncontrolled Keywords: Egfr Gemm Kras Myc exome
Subjects: bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS
diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Hannon lab
Depositing User: Matt Covey
Date: 4 October 2016
Date Deposited: 07 Oct 2016 15:19
Last Modified: 08 Nov 2017 20:02
PMCID: PMC5081629
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33633

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving