Abstract B016: Beyond VEGF: Distinct angiogenic landscapes in ATM and BRCA1/2-mutated ovarian tumors

Abstract Introduction: Ovarian cancer (OC) is a lethal gynecologic malignancy characterized by high genomic instability and poor long-term survival. Germline mutations in BRCA1, BRCA2, and ATM impair DNA repair pathways and contribute to tumor progression. These alterations may also differentially regulate tumor angiogenesis. While anti-VEGF therapies and PARP inhibitors have shown efficacy in OC, their angiogenic targeting is largely limited to VEGFA. The angiogenic profiles of ATM- versus BRCA1/2-mutated tumors remain poorly defined. This study aimed to compare angiogenesis-related gene expression in OC with ATM or BRCA1/2 mutations to identify genotype-specific targets for future anti-angiogenic strategies. Methods: RNA-seq data from dataset GSE131027 (NCBI GEO) were analyzed to compare angiogenic gene expression in advanced ovarian tumors with pathogenic ATM or BRCA1/2 mutations. Samples were stratified by mutation status using provided clinical annotations. Differential expression analysis was performed using the limma-voom pipeline in R. Genes with |logFC| > 1.5 and adjusted p < 0.05 were considered significant. Angiogenesis-related targets were prioritized based on predefined gene sets, and findings were interpreted in the context of established vascular signaling pathways and tumor biology. Results: ATM-deficient tumors showed upregulation of pro-angiogenic genes including PDGFRA, MMP2, CXCL12, THBS2, PDGFRB, PECAM1, and FGF, while VEGFA and FGFR2 were downregulated and enriched in BRCA1/2-deficient tumors. These patterns suggest divergent angiogenic pathways: ATM-mutant tumors rely more on PDGF- and MMP-driven signaling, while BRCA1/2-mutant tumors exhibit VEGF dependence. Correlation analysis highlighted UBIAD1 as potentially permissive for VEGFA activity, given its known role in endothelial survival via vitamin K2 biosynthesis. Conclusion: ATM- and BRCA1/2-deficient OC display distinct angiogenic signatures, with ATM-mutant tumors enriched in PDGF- and MMP-related pathways and BRCA1/2-mutant tumors showing greater VEGF dependency. These findings support the potential for mutation-guided anti-angiogenic therapies beyond VEGF inhibition. Further investigation is needed to fully elucidate the angiogenic signals and mechanistic differences driving vascular remodeling in ATM- versus BRCA1/2-deficient OC, including the potential modulatory role of UBIAD1. Citation Format: Allen Seylani, Yohannes Haile, Assal Sadighian. Beyond VEGF: Distinct angiogenic landscapes in ATM and BRCA1/2-mutated ovarian tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B016.