Wu, Anna M.

Abstract Background: Chronic inflammation is implicated in ovarian carcinogenesis, but how different inflammation-related exposures individually or jointly affect histotype-specific associations remains unclear. Materials and Methods: We pooled data from 16 case-control studies in the Ovarian Cancer Association Consortium to evaluate associations of eight inflammation-related factors (anti-inflammatory: aspirin use, tubal ligation (TL); pro-inflammatory: endometriosis, obesity, lifetime ovulatory cycles (LOC), smoking, pelvic inflammatory disease (PID), polycystic ovary syndrome (PCOS)) with epithelial ovarian cancer (OvC) by histologic subtype. We examined individual associations and clustering of risk factors across histotypes and computed population attributable risk (PAR) for each factor. We assessed additive and multiplicative interactions for exposure combinations. Results: Associations with OvC risk differed by histotype (e.g., high-grade serous: aspirin: OR=0.90; 95%CI 0.82, 0.99; TL: OR=0.80; 95%CI 0.73, 0.88; overall serous: endometriosis: OR=1.17; 95%CI 1.03, 1.31; high LOC: OR=1.42; 95%CI 1.28, 1.58; obesity (low-grade serous): OR=1.50; 95%CI 1.14, 1.98). Clustering analyses showed highly correlated risk profiles in endometrioid and clear cell (r=0.91). High-grade serous and mucinous profiles were moderately correlated with endometrioid and clear cell (r=0.60) tumors. The profile for low-grade serous (r=0.36) tumors was distinct from other histotypes. PAR estimates suggested modifying aspirin use, TL, and LOCs could substantially reduce burdens of endometrioid, clear cell and mucinous tumors. Out of 28 exposure combinations tested in overall OvC and 189 by histotype, we observed 12 interactions. Not using aspirin regularly showed positive additive interactions with obesity and high LOCs, particularly in endometrioid tumors (obesity relative excess risk due to interaction (RERI)=0.74, 95%CI 0.31, 1.18; Pint=0.001 for; LOCs RERI=0.80, 95%CI 0.03, 1.56; Pint=0.04). Not using aspirin regularly also showed a positive additive interaction with endometriosis in clear cell tumors (RERI=1.77, 95%CI 0.03, 3.52; Pint=0.05). Lack of TL showed positive interactions with obesity in endometrioid (RERI=0.86, 95%CI 0.17, 1.53; Pint=0.01) and mucinous (RERI=1.10, 95%CI 0.23, 1.97; Pint=0.01) tumors, while negative additive interactions were observed for smoking and endometriosis in endometrioid tumors (RERI=-1.12, 95%CI -2.19, -0.05; Pint=0.04). A multiplicative interaction was observed between obesity and endometriosis in mucinous tumors (Pint=0.01). Conclusion: The findings suggest ovarian tumorigenesis is strongly shaped by pro- and anti-inflammatory pathways that act largely independently. Further examining these pathways may clarify the origins of histotype heterogeneity and guide prevention strategies. Citation Format: Maxwell Akonde, Britton Trabert, SHELLEY TWOROGER, Allan Jensen, Kathryn L. Terry, Joshua Sampson, Hoda Anton-Culver, David Bowtell, Elisa V. Bandera, Angela Brooks-Wilson, Andrew Berchuck, Daniel William Cramer, Linda S. Cook, Julie M. Cunningham, Jennifer A. Doherty, Ellen L. Goode, Marc T. Goodman, Holly Ruth Harris, Susanne K. Kjaer, Nhu Le, Alice Wen-Ron Lee, Francesmary Modugno, Kirsten B. Moysich, Celeste Pearce, Malcolm C. Pike, Harvey A. Risch, Mary A. Rossing, Joellen M. Schildkrau, Daniel O. Stram, Rebecca Sutphen, David Van Den Berg, Penelope M. Webb, Anna Wu, Argyrios Ziogas, Nicolas A. Wentzensen. Inflammation-related exposures and histotype- specific ovarian cancer risk in the Ovarian Cancer Association Consortium (OCAC) [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 6261.

Abstract Improving risk prediction and prevention strategies through identifying new susceptibility genes for non-high-grade serous ovarian cancer (non-HGS) would represent an important advance in reducing incidence and mortality. Epithelial ovarian cancer (EOC) has five main histotypes that have distinct pathologies, molecular changes, clinical characteristics, and tissues of origin. They are classified as high-grade serous (HGS), low-grade serous (LGS), clear-cell (CCC), endometrioid (END), and mucinous (MUC). A family history of breast or ovarian cancer is the strongest single risk factor for EOC. Germline mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2 confer EOC risks of 44% and 17% by age 80, respectively. Only 40% of the excess familial risk is known, suggesting there are many other susceptibility genes yet unidentified. The non-HGS histotypes are poorly studied due to limited sample size within individual studies. Thus, families of cases with non-HGS tumors have few risk prediction options. Whole-exome sequencing (WES) analysis was performed on 251 non-HGS cases (56 LGS, 55 CCC, 117 END, 23 MUC). Cases were screened negative for BRCA1/2 mutations and selected for a family history of ovarian or breast cancer, or young onset (<45 years) of ovarian cancer. WES identified 1,278 genes with rare predicted truncating mutation in at least one case. Predicted truncating mutations in cases were compared to 171,584 controls from the Exome Aggregation Consortium (ExAC) and the Genome Aggregation Database (gnomAD). Gene-set enrichment analysis showed enrichment for genes involved in the DNA repair pathway (p=3.08 × 10−7). Twenty-five candidate genes (including 4 DNA repair genes) were selected for validation by targeted sequencing. Five genes important in HGS (BRIP1, FANCM, PALB2, RAD51C, RAD51D) as well as two additional candidates (XRCC2 and XRCC3) were also sequenced. Targeted sequencing was performed on 1,779 cases (669 END, 356 CCC, 327 LGS, 427 MUC) and 1,863 controls from studies in the Ovarian Cancer Association Consortium (OCAC). Library preparation and target enrichment was performed using the Fluidigm Juno System and Illumina sequencing was performed on a NovaSeq 6000 Sequencing System. A case-control analysis of predicted truncating variants in the 32 genes was performed. Using a minimum alternate allele frequency of 30%, we identified a higher frequency of mutations in non-HGS cases than controls in ERCC6 (p=0.034) and IL31RA (p=0.034). ERCC6 is involved in DNA repair and IL31RA is a cytokine receptor. Sanger sequencing validation of variants to confirm these results is ongoing. Several other genes showed suggestive higher frequencies of mutations in cases than controls. A larger case control analysis will be performed to confirm those findings. Identifying novel susceptibility genes for non-HGS may have clinical impact by reducing disease-associated mortality through improving risk prediction, identifying prevention strategies, and developing new targeted treatments. Citation Format: Marina Pavanello, Ed Dicks, Honglin Song, Amir Ariff, Adelyn Bolithon, Maria P. Intermaggio, Mark Pinese, Kirsten Moysich, Kunle O. Odunsi, Ellen Goode, David D. Bowtell, Peter Fasching, Jennifer A. Doherty, Francesmary Modugno, Susanne K. Kjær, Penelope M. Webb, Anna Wu, Anna deFazio, Ovarian Cancer Association Consortium, Paul James, Deepak Subramanian, Ian Campbell, Simon A. Gayther, Paul D.P. Pharoah, Susan J. Ramus. Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B37.