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)
Preview |
PDF (Paper)
Hannon PNAS 2016.pdf - Published Version Download (946kB) | Preview |
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: | https://repository.cshl.edu/id/eprint/33633 |
Actions (login required)
 |
Administrator's edit/view item |