Abstract A009: Mutation Matters: ATM and BRCA1/2 Shape Divergent Coagulopathy Programs in Pancreatic Cancer

Introduction: Early onset pancreatic ductal adenocarcinoma (PDAC) is on the rise, and inherited germline mutations in DNA damage repair pathways, including ATM and BRCA1/2, are increasingly recognized as important drivers. Cancer-associated coagulopathy is a leading cause of morbidity and mortality in PDAC, yet it remains unclear how distinct germline mutations influence thrombotic biology. Understanding whether ATM- versus BRCA1/2-driven PDAC tumors create unique coagulation signatures is critical for refining thromboprophylaxis strategies and for identifying novel therapeutic targets. Methods: We analyzed bulk RNA sequencing data from PDAC patient samples carrying germline ATM or BRCA1/2 mutations using the publicly available Gene Expression Omnibus dataset GSE193057. Raw counts were processed and normalized to transcripts per million (TPM). Genes related to the coagulation cascade, including clotting factors and fibrinogen subunits, were compared between mutation cohorts. Expression values were log2-transformed and averaged to highlight mutation-specific transcriptional differences across the coagulation pathway. Results: Transcriptomic analysis revealed divergent coagulation profiles. ATM-mutated tumors showed higher expression of Factor XI (log2 2.1 vs 0.2), Factor XIII A (4.6 vs 0.2), and fibrinogen chains FGA (1.0 vs 0.3), FGB (0.3 vs 0.7), and FGG (1.1 vs 0.2). In contrast, BRCA1/2-mutated tumors expressed markedly elevated Factor XII (8.9 vs 0.2), Factor VIII (3.2 vs 1.2), and Prothrombin (1.4 vs 0.1). Tissue Factor (Factor III) and Factor V were highly expressed in both cohorts, with greater proportion in BRCA1/2-mutated tumors (9.1 vs 6.9). Conclusions: Distinct germline contexts shape the coagulation landscape in PDAC through divergent mechanisms. ATM mutation appears to favor fibrin network stabilization via intrinsic pathway activation, whereas BRCA1/2 mutation preferentially enhances thrombin flux through contact and extrinsic pathway signaling. These mechanistic differences may underlie variable thrombotic risk across mutation carriers and highlight opportunities for mutation-specific thromboprophylaxis and mechanistic intervention. Citation Format: Allen Seylani, Allen Luo, Shane Handelsman, Assal Sadighian. Mutation Matters: ATM and BRCA1/2 Shape Divergent Coagulopathy Programs in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr A009.