Abstract A009: Mutation Matters: ATM and BRCA1/2 Shape Divergent Coagulopathy Programs in Pancreatic Cancer
Bibliographic record
Abstract
Abstract 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".