Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers

Abstract The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are co-altered in RAS mutant tumors, we analyzed targeted next-generation sequence data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutational burden and mutational signatures on co-mutation patterns. These analyses revealed differential RAS prevalence and co-mutations with non-RAS genes in a cancer lineage and context-dependent manner, with differences across age, sex and ethnic groups. Allele specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multi-omic analyses of 10,217 tumors from TCGA revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS mutant tumors. The distinct genomic tracks discovered in RAS mutant tumors reflected differential clinical outcomes in the TCGA cohort and in an independent cohort of patients with KRAS G12C mutant non-small cell lung cancer that received immunotherapy containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS mutant allele-directed therapies with targeted therapies and immunotherapy.