Abstract 2195: A tissue atlas of oncogenic RAS mutation

Abstract Despite over 50 possible oncogenic RAS mutations, cancers tend to have a bias towards a specific subset unique to each cancer type. As RAS mutations could arise from selection of an ideal level (quantitative) or type (qualitative) of oncogenic signaling, we generated four conditional Kras alleles with different oncogenic mutations, G12D or Q61R, coded with native rare or common codons to induce low or high protein expression to separate these two types of signaling. These alleles were crossed into a Rosa26-CreER background and globally activated, revealing tissues sensitive to quantitative signaling regulated by the RAS biochemical activity, qualitative signaling regulated by the specific mutation, and either both or none of these two types of signaling. Bulk RNAseq analysis further revealed that each allele induced a different cellular response, with the weakest allele induce transcriptional features of a plastic state while the strongest allele had all the transcriptional hallmarks of high oncogenic signaling and a stress response. In conclusion, this approach provides a mutational atlas of tissues dependent upon quantitative signaling, qualitative signaling, or both forms of signaling for tumorigenesis, as well as tissues generally resistant to oncogenic RAS. This tissue atlas can thus serve to define how specific cancers are initiated, and in turn, how to prevent such initiation events from taking hold to lead a normal cell down the path of tumorigenesis, which has important clinical implications for early cancer detection and prevention measures. Citation Format: Ozgun Erdogan, Christopher Counter. A tissue atlas of oncogenic RAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2195.