Abstract
RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a 'tropism' towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine Kras gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.
Highlights
The RAS genes are mutated in a fifth or more of human cancers (Prior et al, 2020), which is well established to be tumorigenic (Pylayeva-Gupta et al, 2011)
To explore the effect of oncogenic signaling levels on the selection of initiating oncogenic mutations, we genetically inactivated p53 to inhibit the cellular response to oncogenic stress or enhanced Kras translation to increase oncogenic activity in mice exposed to urethane
The SftpcCreER/CreER;Trp53flox/flox genotype was chosen as injection of tamoxifen into such mice leads to recombination and inactivation of the endogenous Trp53flox alleles in the type II alveolar cells of the lung (Xu et al, 2012), which is reported to suppress oncogene-induced senescence/ apoptosis induced by oncogenic Kras in this organ (Feldser et al, 2010; Junttila et al, 2010)
Summary
The RAS genes are mutated in a fifth or more of human cancers (Prior et al, 2020), which is well established to be tumorigenic (Pylayeva-Gupta et al, 2011). In regards to the second genetic change, we evaluated retaining or conditionally inactivating the Trp gene in the lung, which has been shown to suppress oncogenic stress due to high mutant Kras expression in this tissue in vivo (Feldser et al, 2010; Junttila et al, 2010) Using this approach, we show here that the canonical Q61L/R mutations are selected against in the more highly expressed Krasex3op allele in urethane-induced tumors, even though the carcinogen favors this mutation. Tumors characterized by Q61 mutations or the less active G12 mutants when coupled with allelic imbalance exhibited similar transcript levels of three genes known to be activated by oncogenic RAS, suggesting a similar degree of oncogenic signaling Taken together, these data support a narrow window of signaling conducive to initiate tumorigenesis in a normal cell. Krasex3op allele on urethane-mediated lung tumorigenesis in the absence of p53
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