Abstract RAS family oncogenes (KRAS, NRAS, HRAS) are critical drivers of tumorigenesis across multiple cancer types, yet the pan-cancer landscape of RAS mutations and their therapeutic implications remains incompletely characterized. We performed a systematic meta-analysis integrating genomic, transcriptomic, and clinical data from over 30, 000 patient samples across TCGA, ICGC, and CPTAC repositories. Using random-effects meta-regression and survival modeling, we identified cancer-specific and pan-cancer mutational hotspots, including KRAS G12C, NRAS Q61, and HRAS Q61 variants, and assessed their correlation with treatment response to targeted therapies, immunotherapy, and novel RAS-directed agents. Subgroup analyses revealed distinct mutation-response patterns across colorectal, pancreatic, lung, and melanoma cohorts, highlighting therapeutic vulnerabilities unique to each tumor type. Our findings provide a comprehensive, evidence-based framework for precision oncology, offering actionable insights for clinical trial design, drug development, and policy guidance in global cancer therapeutics. Citation Format: Shivi Kumar, Deirde Richardson. Pan-Cancer Systematic Meta-Analysis of RAS Oncogene Mutational Landscapes and Therapeutic Vulnerabilities abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B003.
Kumar et al. (Thu,) studied this question.