Abstract 7145: The pan-cancer landscape of <i>RIT1</i> genetic alterations

Abstract Background: Advancements in drug design have resulted in the development of approved and investigational agents targeting KRAS-driven tumors. RIT1 is a GTPase protein that shares homology and oncogenic activation mechanisms with KRAS and plays a role in cell division and resistance to apoptosis. In this study, we aimed to characterize the landscape of RIT1 alterations across a pan-cancer cohort to assess its frequency and potential as an oncogenic driver. Methods: Tumor content, ploidy and allelic specific copy number of 86, 039 tumor-normal matched samples sequenced clinically with a targeted sequencing panel (MSK-IMPACT) were analyzed with FACETS. Low purity (&amp;lt;20%) and indetermined copy number samples were excluded. Presence of RIT1 amplifications (Amp), structural variants, oncogenic mutations (Mut), and concurrent OncoKb oncogenic/likely-oncogenic alterations in other genes were evaluated. Co-occurrence and mutual-exclusivity (Co-Me) analyses were performed using DISCOVER. RIT1-altered samples were evaluated for genomic complexity compared to wild-type (WT) samples. False discovery rate correction was applied when appropriate. Results: After removing low-quality samples, 63, 270 cancer samples were included, and 1.32% (n=838) were found to harbor RIT1 oncogenic alterations. Most RIT1-alterations observed were Amps (735/838) followed by somatic mutations (Muts) (83/838), concomitant Mut and Amp (2/838) and structural variants (18/838). The most frequent RIT1 Mut was p.M90I (n=40), followed by p.F82C (n=17), p.A77T (n=11) and R122Q (n=9).Uterine carcinosarcomas (5.5%), hormone receptor-positive breast cancer (4.9%) and triple-negative breast cancer (4.7%) had the highest prevalence of RIT1 alterations. Restricting the analysis only to Muts, lung adenocarcinoma (LUAD) (n=15; 0.22%) and bladder cancers (n=13; 0.51%) had the highest number of oncogenic RIT1 Muts. RIT1-mutant samples had higher TMBs than RIT1-WT samples (p&amp;lt;0.01). This association was conserved when accounting for histology in bladder cancer and LUAD (p&amp;lt;0.01). RIT1 Amps were associated with higher fraction of genome altered (p&amp;lt;0.01) and co-occurred with amps of neighboring genes NTRK1 (p&amp;lt;0.01) and AKT3 (p&amp;lt;0.01) across most tumor types. DISCOVER assisted Co-Me analysis identified RIT1 Muts as mutually exclusive with EGFR Muts in LUAD (p&amp;lt;0.01). Among RIT1-mutant samples, 10/15 (66%) LUADs harbored RIT1 as the sole identifiable oncogene driver alteration, whereas only 3/13 (23%) bladder cancers were otherwise driver negative. Conclusion: RIT1 alterations appear to be rare across most tumor types. Higher TMB and rarity of RIT1 Muts and the observation of RIT1 Amps frequently co-amplified with other chromosome 1 arm q genes, suggest that these alterations might be primarily passengers. These results have implications for stakeholders interested in developing potential therapies for RIT1 as the landscape of these alterations has not been previously explored. Citation Format: Matteo Repetto, Pier Selenica, Soo-Ryum Yang, Britta Weigelt, Alexander Drilon. The pan-cancer landscape of RIT1 genetic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7145.