Abstract 3585: A body mass index polygenic risk score (PRSBMI) and obesity-related cancer risk among women in the Hispanic Community Health Study/Study of Latinos.

Abstract Background. Obesity is associated with an increased risk of cancer including cancers of the colon and rectum, endometrium, and breast among women. Polygenic risk scores (PRS), which sum the effects of risk variants, estimate an individual’s genetic predisposition to complex phenotypic traits, such as obesity. We constructed a PRS for body mass index (PRSBMI) and examined whether the PRSBMI was associated with the risk of obesity-related cancers (ORCs) among Hispanic/Latina women. We also examined whether BMI moderated or mediated the association between PRSBMI and ORC risk. Methods. This prospective cohort study included 8,380 Hispanic/Latina women (mean age at baseline=41.8±0.3 years) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). At baseline in 2008-2011, height and weight were measured and used to compute BMI, and participants provided blood samples for genotyping. The PRSBMI was constructed using previously published weights downloaded from the polygenic score (PGS) catalog. The incidence of 13 obesity-related cancers diagnosed from baseline through 2021 was ascertained through linkages with four state cancer registries (n=223 incident ORCs were diagnosed over a mean follow-up of 10.8 years). Survey multivariable Cox regression models estimated the associations (hazard ratios, HRs, and 95% confidence intervals, CIs) between the PRSBMI (per standard deviation, SD) and ORC risk overall and by BMI (25 vs. ≥25 kg/m2). Survey multivariable Cox regression and linear regression models tested the mediating effect of BMI (continuous, kg/m2) on the association between PRSBMI (per SD) and ORC risk. Results. In stratified analyses, a 1-SD increase in the PRSBMI was associated with an ORC HR of 0.74 (95%CI=0.56-0.97) among women with BMI30 kg/m2, but not among women with a BMI≥30 kg/m2 (HR=0.95; 95%CI=0.68-1.33; PInteraction=0.15). In mediation analyses, PRSBMI was significantly associated with BMI (βa=1.86; 95%CI=1.66-2.06); BMI was significantly associated with ORC risk, adjusting for PRSBMI (βb=0.07; SE=0.01; HR=1.07; 95%CI=1.05-0.19); and BMI significantly mediated the association between PRSBMI and ORC risk (indirect effect, βa*βb=0.13; 95%CI=0.07-0.19). Conclusion. Genes predisposing women to a higher BMI may primarily impact ORC risk through BMI. These results highlight the importance of weight management for cancer prevention among Hispanic/Latina women. Citation Format: Humberto Parada, Tamar Sofer, Margaret Pichardo, Krista M. Perreira, Laura Zhou, Frank J. Penedo, Amber Pirzada, Martha Daviglus, Gregory A. Talavera, Linda C. Gallo. A body mass index polygenic risk score (PRSBMI) and obesity-related cancer risk among women in the Hispanic Community Health Study/Study of Latinos 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 3585.