Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108807 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1811091814459899904 |
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| author | Politi, Katerina Song, Xiaoling Pirun, Mono Kim-Kiselak, Caroline Platt, James T. Lee, Emily Hodges, Emily Rosebrock, Adam P. Bronson, Roderick T. Socci, Nicholas D. Hannon, Gregory J. Varmus, Harold McFadden, David Glenn Bhutkar, Arjun Chen, Frances K. Santiago, Philip M. Jacks, Tyler E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Politi, Katerina Song, Xiaoling Pirun, Mono Kim-Kiselak, Caroline Platt, James T. Lee, Emily Hodges, Emily Rosebrock, Adam P. Bronson, Roderick T. Socci, Nicholas D. Hannon, Gregory J. Varmus, Harold McFadden, David Glenn Bhutkar, Arjun Chen, Frances K. Santiago, Philip M. Jacks, Tyler E. |
| author_sort | Politi, Katerina |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:08:27Z |
| format | Article |
| id | mit-1721.1/108807 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:08:27Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1088072022-09-29T12:57:20Z Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma Politi, Katerina Song, Xiaoling Pirun, Mono Kim-Kiselak, Caroline Platt, James T. Lee, Emily Hodges, Emily Rosebrock, Adam P. Bronson, Roderick T. Socci, Nicholas D. Hannon, Gregory J. Varmus, Harold McFadden, David Glenn Bhutkar, Arjun Chen, Frances K. Santiago, Philip M. Jacks, Tyler E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT McFadden, David Glenn Bhutkar, Arjun Chen, Frances K. Santiago, Philip M. Jacks, Tyler E. 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. United States. National Institutes of Health (NCI K08 160658) 2017-05-11T14:29:28Z 2017-05-11T14:29:28Z 2016-10 2016-04 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/108807 McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M. et al. “ Mutational Landscape of EGFR-, MYC-, and Kras-Driven Genetically Engineered Mouse Models of Lung Adenocarcinoma.” Proceedings of the National Academy of Sciences 113, no. 42 (October 2016): E6409–E6417. © 2016 National Academy of Sciences https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1073/pnas.1613601113 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Politi, Katerina Song, Xiaoling Pirun, Mono Kim-Kiselak, Caroline Platt, James T. Lee, Emily Hodges, Emily Rosebrock, Adam P. Bronson, Roderick T. Socci, Nicholas D. Hannon, Gregory J. Varmus, Harold McFadden, David Glenn Bhutkar, Arjun Chen, Frances K. Santiago, Philip M. Jacks, Tyler E. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title | Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title_full | Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title_fullStr | Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title_full_unstemmed | Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title_short | Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma |
| title_sort | mutational landscape of egfr myc and kras driven genetically engineered mouse models of lung adenocarcinoma |
| url | http://hdl.handle.net/1721.1/108807 https://orcid.org/0000-0001-5785-8911 |
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