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.