RT Journal Article SR Electronic T1 The mutational landscape of EGFR-, MYC-, and Kras- driven genetically-engineered mouse models of lung adenocarcinoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 048058 DO 10.1101/048058 A1 David G. McFadden A1 Katerina Politi A1 Arjun Bhutkar A1 Frances K. Chen A1 Xiaoling Song A1 Mono Pirun A1 Philip M. Santiago A1 Caroline Kim A1 James T. Platt A1 Emily Lee A1 Emily Hodges A1 Adam P. Rosebrock A1 Roderick Bronson A1 Nicholas D. Socci A1 Gregory Hannon A1 Tyler Jacks A1 Harold Varmus YR 2016 UL http://biorxiv.org/content/early/2016/04/11/048058.abstract AB Genetically-engineered mouse models (GEMMs) of cancer are increasingly being utilized to assess putative driver mutations identified by large scale sequencing of human cancer genomes. In order 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 EGFR, mutant Kras or by overexpression of MYC. Tumors from EGFR- and Kras- driven models exhibited respectively 0.02 and 0.07 non-synonymous mutations/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 to 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.