title: Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.
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.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139; david.mcfadden@utsouthwestern.edu tjacks@mit.edu katerina.politi@yale.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: McFadden
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510; Section of Medical Oncology, Department of Medicine, Yale University School of Medicine, New Haven, CT 06510; Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510; david.mcfadden@utsouthwestern.edu tjacks@mit.edu katerina.politi@yale.edu.
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Frances K
authors.initials: FK
authors.lastname: Chen
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.affiliation: Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Mono
authors.initials: M
authors.lastname: Pirun
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Santiago
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kim-Kiselak
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Emily
authors.initials: E
authors.lastname: Lee
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Emily
authors.initials: E
authors.lastname: Hodges
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Rosebrock
authors.affiliation: Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, MA 01536.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hannon
authors.affiliation: David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; david.mcfadden@utsouthwestern.edu tjacks@mit.edu katerina.politi@yale.edu.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.affiliation: Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics*; D018628:Gene Dosage; D016259:Genes, myc; D011905:Genes, ras; D055106:Genome-Wide Association Study; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D012372:ROC Curve; D000073359:Exome Sequencing
chemical_list: D002273:Carcinogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D066246:ErbB Receptors
keywords: EGFR; GEMM; KRAS; MYC; exome