Abstract 1429: Stress-responsive genomic alterations reveal a bi-directional relationship between PTSD biology and breast cancer aggressiveness.

Abstract Background: Breast cancer (BrCa) and post-traumatic stress disorder (PTSD) exhibit a complex, bidirectional relationship. While cancer diagnosis and treatment can induce PTSD, emerging epidemiologic data indicate that pre-existing psychological stress or PTSD may also elevate the risk of developing breast cancer or accelerate tumor progression. The biological mechanisms underlying this interaction remain unclear. We hypothesized that tumor-intrinsic alterations in stress-responsive genes may provide molecular insight into this connection. Methods: We analyzed 17,605 breast tumors using cBioPortal/TCGA datasets and compared them with a 95,474-sample pan-cancer reference. PTSD- and stress-related over sixty genes were curated from published literature and included: TG, CYP11B1, CYP11B2, CRH, NR3C1, SLC6A4, PRKCA, CHRNA6, RGS2, DRD2, BDNF, FKBP5, SLC6A2, TPH2, and others. Copy number alterations, co-amplification patterns, and clinical outcomes (including metastatic progression) were evaluated. Results: Stress-related genes exhibited significantly enriched copy number amplifications in breast cancer compared with a pan-cancer reference cohort. Across 17,605 BrCa tumors, more than sixty PTSD-, mood-, and stress-endocrine-associated genes showed recurrent CNAs. Key alterations included TG (19%), CYP11B1/CYP11B2 (16%), RGS2 (12%), CRH (10%), PRKCA (9%), and CHRNA6 (8%), markedly higher BrCa than their frequency across 95,474 tumors from all cancer types (2-5%). TG-amplified tumors demonstrated coordinated co-amplifications involving 8q24 (MYC/PVT1) and 1q32, along with characteristic 8p22 deletions, genomic features strongly associated with aggressive disease biology. Exploratory clinical annotation further showed that TG- or CYP11B-gated BrCa cohorts exhibited rapid metastatic progression, with a median time to metastasis <10 months. Together, these findings identify a robust stress-tumor genomic axis in breast cancer and highlight Thyroglobulin (TG) and Corticotropin-Releasing Hormone (CRH) as high-priority candidates for development as objective, noninvasive serum biomarkers. Conclusion: Large-scale civilian tumor genomic analyses reveal that stress-responsive and PTSD-linked genes are recurrently amplified in breast cancer and co-cluster with high-risk oncogenic regions. These findings support a biological model in which chronic stress/PTSD and breast cancer aggressiveness intersect through shared neuroendocrine and GPCR-linked molecular pathways. This stress/tumor axis may help explain both PTSD arising after a breast cancer diagnosis and stress-associated increases in breast cancer risk or progression. These insights establish a foundation for developing objective biomarkers and mechanistic studies exploring the PTSD-BrCa interface. Citation Format: Alakesh Bera, Meera Srivastava. Stress-responsive genomic alterations reveal a bi-directional relationship between PTSD biology and breast cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1429.