Elucidating the Mechanisms Underlying the Mutational Bias of RAS Genes in Cancer Using a Chemical Carcinogenesis Mouse Model

Missense oncogenic mutations in the RAS genes are found in around 20% of all human cancers, which are known to be tumorigenic. Despite scores of different oncogenic RAS mutations detected in human cancers, these mutations have distinct patterns, often with a specific set of mutations unique to each cancer type. As RAS mutations can initiate cancer, elucidating the mechanism underlying RAS mutation patterns could inform on the origin of cancer. While capturing the moment cancer begins is not tractable in humans, the process of establishing RAS mutation patterns is recapitulated in mice exposed to the environmental carcinogen urethane, which induces lung tumors driven by one specific Ras mutation. I therefore captured the mutation spectrum of Ras genes after urethane exposure, which revealed that this bias appeared to be a product of the mutagenic preference of the carcinogen as well as high Kras expression. However, when endogenous Kras expression was increased, this mutational bias was shifted to other mutations. I show that in this setting a p53-dependent selection for an optimal signaling level becomes the dominant factor in the bias towards a specific Kras mutation. Collectively, these findings suggest that a multifactorial process shapes the mutational spectrum of RAS genes in cancer.