Abstract IA14: Rare codons capacitate Kras-driven de novo tumorigenesis

The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. We discovered that this gene has the unusual feature of having a bias towards rare codons, which are associated with poor translation. Indeed, by changing rare codons to common the amount of KRAS mRNA detected in the heavy fraction by polysome profiling was reduced in lockstep with an increase in protein expression. This poor translation of KRAS has a direct impact on oncogenesis, but curiously, not in the direction one might expect. Specifically, we treated mice in which rare codons in the Kras gene were changed to common with a carcinogen known to induce lung tumors characterized by oncogenic Q61L/R mutations in Kras . Interestingly, these mice exhibited a reduction in tumor burden. Moreover, not only was the altered Kras allele mutated less often, but when it was mutated, completely different mutations were detected, namely G12V/D. We attribute this to a selection against the stronger Q61L/R mutations in favor of weaker G12V mutations in the higher expressed modified Kras allele, as strong oncogenic signaling leads to growth arrest instead of proliferation. As such, the poor translation of KRAS may reduce the chance that an oncogenic mutation induces growth arrest, which perhaps is related to the high frequency this gene is mutated in human cancers or even why specific KRAS mutations map to certain cancers. Citation Format: Nicole L.K. Pershing, Benjamin L. Lampson, Christopher M. Counter. Rare codons capacitate Kras-driven de novo tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA14.