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 coaltered in RAS-mutant
tumors, we analyzed targeted next-generation sequencing 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 mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a
cancer lineage-dependent 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 multiomic analyses of 10,217
tumors from The
Cancer Genome Atlas (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 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.
SIGNIFICANCE: The complex genomic landscape of RAS-mutant
tumors is reflective of selection processes in a
cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.