Abstract Background: Distress increases the risk of developing epithelial ovarian cancer (EOC). This can lead to the activation of the sympathetic nervous system (SNS) and the release of norepinephrine (NE). NE promotes inflammation, angiogenesis, and cell motility, which influence early and late stages of tumor progression. Widowhood is one form of chronic psychosocial stress that is associated with an increase in EOC risk. We hypothesize that women who experienced widowhood prior to EOC diagnosis will have higher tumor gene expression of inflammation-related and immune suppression pathways when compared to women who are married. Methods: RNA sequencing was performed on 167 high-grade serous or poorly differentiated ovarian cancer tumors from the Nurses’ Health Study (NHS), NHSII, and the New England Case-Control study who had information on pre-diagnosis marital status. The primary exposure was ever reported widowhood up to 1 year before diagnosis. Linear regression was used to identify differentially expressed genes associated with widowhood, adjusted for age. Gene set enrichment analysis (GSEA) using the Cancer Hallmarks, KEGG, and Reactome databases was employed to identify biological pathways associated with widowhood. Results: Five genes (KCNE3, ACHE, C3orf52, RPL19P9, and AC116366) were significantly upregulated in the ovarian tumors of widowed versus married individuals. The top upregulated genes are associated with wound healing and cancer progression. Two genes (GABBR2 and RPS3AP29) were significantly downregulated and have been demonstrated to be involved in inhibitory neurotransmission and elevated tumor immune cell infiltration. GSEA identified six pathways that exhibited significant associations with widowhood, specifically related to inflammation (TNF-α), proliferation (G2M checkpoint), and tumor immunity (interferon-α and γ response). Conclusions: Our results provide insight into biological pathways that link widowhood to ovarian cancer development, particularly through inflammatory and tumor immunity pathways. Citation Format: Jaileene Perez Morales, Kathryn Berns, Cassandra Copp, Joseph Grieco, Mark K. Townsend, Steven A. Eschrich, Guillermo Armaiz-Pena, Lauren Cole Peres, Shelley TWOROGER. Association between widowhood and ovarian tumor gene expression 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 2325.
Morales et al. (Fri,) studied this question.