Carcinogen and Genetic NSCLC Models Exhibit Distinct Mutation Spectra

Whole-genome sequencing of patient tumors has revealed mutation signatures that may be attributed to exposure to environmental agents. To further investigate this idea, Westcott and colleagues performed whole-exome sequencing to compare the mutation signatures of genetic and carcinogen-induced mouse models of KRAS-driven non–small cell lung cancer (NSCLC). Adenomas from mice treated with the carcinogens methyl-nitrosourea (MNU) or urethane exhibited a greater incidence of single-nucleotide variations (SNV) compared with adenomas that spontaneously formed following genetic activation of Kras (Kras^LA2), recapitulating differences observed in human NSCLC tumors arising in smokers and nonsmokers. In addition, MNU-induced and urethane-induced tumors displayed distinct types of SNV signatures, consistent with the mutation spectra of the initiating carcinogen. Intriguingly, urethane-induced tumors harbored different mutations of KRAS codon 61 in wild-type mice as compared with Kras heterozygous mice, suggesting that germline differences in Kras expression contribute to Kras mutation selection. Despite similar histology to MNU-induced adenomas and the presence of the same Kras^G12D mutation, Kras^LA2 adenomas had 15-fold fewer SNVs but frequent copy-number alterations (CNA) and aneuploidy, which were not detected in carcinogen-induced adenomas. Additional analysis revealed that only carcinogen-induced tumors, but not Kras^LA2 adenomas, harbored SNVs in known driver genes, whereas Kras^LA2 adenomas exhibited CNAs in genes commonly mutated in carcinogen-induced tumors, demonstrating fundamental differences in genomic alterations in these models. Furthermore, carcinogen-induced adenocarcinomas were enriched for SNVs in driver genes and C>T transitions, a signature of genomic instability, compared with adenomas. Moreover, comparison of carcinogen-induced mouse mutations with whole-exome sequencing of human lung adenocarcinomas identified similarities in frequently mutated driver genes. Taken together, these data may provide a better understanding of the mutational landscape in human tumors and suggest that carcinogen-induced mouse tumors may recapitulate the mutational heterogeneity of human tumors.

Westcott PM, Halliwill KD, To MD, Rashid M, Rust AG, Keane TM, et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 2014 Nov 2 [Epub ahead of print].