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

doi:10.1073/pnas.1613601113

	Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma
	McFadden, David G.1,12,13; Politi, Katerina 2,3,4; Bhutkar, Arjun 1; Chen, Frances K.1; Song, Xiaoling4,14 ; Pirun, Mono 5; Santiago, Philip M.1; Kim-Kiselak, Caroline 1; Platt, James T.4; Lee, Emily 6; Hodges, Emily 6; Rosebrock, Adam P.6,15; Bronsong, Roderick T.7; Socci, Nicholas D.5; Hannon, Gregory J.6,8,16; Jacks, Tyler 1,9,10; Varmus, Harold 11,17
	2016-10-18
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	0027-8424
卷号	113 期号:42 页码:E6409-E6417
发表状态	已发表
DOI	10.1073/pnas.1613601113
摘要	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.
关键词	KRAS EGFR MYC GEMM exome
收录类别	SCI
语种	英语
资助项目	Cancer Research UK[21143]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000385610400014
出版者	NATL ACAD SCIENCES
WOS关键词	GENOMIC LANDSCAPE ; CANCER ; PROGRESSION ; SENSITIVITY ; ONCOGENE ; REARRANGEMENTS ; TUMORIGENESIS ; MAINTENANCE ; ACTIVATION ; EXPRESSION
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1668
专题	免疫化学研究所_特聘教授组_干细胞生物学实验室免疫化学研究所_特聘教授组_抗体化学实验室
通讯作者	McFadden, David G.; Politi, Katerina
作者单位	1.MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA 2.Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA 3.Yale Univ, Sch Med, Dept Med, Sect Med Oncol, New Haven, CT 06510 USA 4.Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA 5.Mem Sloan Kettering Canc Ctr, Bioinformat Core, New York, NY 10065 USA 6.Cold Spring Harbor Lab, Watson Sch Biol Sci, POB 100, Cold Spring Harbor, NY 11724 USA 7.Tufts Univ, Sch Med & Vet Med, Dept Pathol, North Grafton, MA 01536 USA 8.Cold Spring Harbor Lab, Howard Hughes Med Inst, POB 100, Cold Spring Harbor, NY 11724 USA 9.MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA 10.MIT, Dept Biol, Cambridge, MA 02142 USA 11.Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10065 USA 12.UT Southwestern Med Ctr Dallas, Div Endocrinol, Dept Internal Med, Dallas, TX 75235 USA 13.UT Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75235 USA 14.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 15.Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 1A1, Canada 16.Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England 17.Cornell Univ, Meyer Canc Ctr, Weill Cornell Med, New York, NY 10065 USA
推荐引用方式 GB/T 7714	McFadden, David G.,Politi, Katerina,Bhutkar, Arjun,et al. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2016,113(42):E6409-E6417.
APA	McFadden, David G..,Politi, Katerina.,Bhutkar, Arjun.,Chen, Frances K..,Song, Xiaoling.,...&Varmus, Harold.(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.
MLA	McFadden, David G.,et al."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(2016):E6409-E6417.