Abstract A064: Racial disparities in folate metabolism, genetic variants, and prostate cancer aggressiveness

Background: African American (AA) men experience a 70% higher incidence and disproportionately aggressive forms of prostate cancer compared to European American (EA) men. Folate, critical for DNA synthesis and methylation, may influence cancer outcomes, especially in populations with distinct genetic and dietary profiles. We investigated the role of dietary folate intake and gene variants in folate metabolism in contributing to racial disparities in prostate cancer aggressiveness. Methods: Data from 1,497 prostate cancer cases (722 AA, 775 EA) from the North Carolina-Louisiana Prostate Cancer Project were analyzed. Dietary intakes of natural folate, synthetic folate, and dietary folate equivalents (DFE) were measured using validated food frequency questionnaires. SNPs in folate metabolism genes (rs758711/MTHFD1, rs4652/AGER, and MTHFR 677TT) were genotyped from blood samples. Multivariable logistic regression models assessed associations between folate intake, SNPs, and prostate cancer aggressiveness, stratified by race and adjusted for age, BMI, energy intake, education, smoking, screening history, and family history. Results: AA men had higher folate intake and a significantly greater likelihood of high tumor aggressiveness (31.6% vs. 21.7% in EA, p<0.001). Among AA men, high intake of DFE (adjusted odds ratio (adjOR)=2.09), synthetic folate (adjOR=2.25), and natural folate (adjOR=2.19) were associated with increased odds of aggressive disease. These associations were attenuated or reversed in EA men. Genetically, AA men with the rs758711 CC variant exhibited greater increases in plasma folate at high synthetic folate intake. The rs4652 SNP showed a threshold effect in AA men, and MTHFR 677TT was linked to consistently lower plasma folate levels, particularly in AA men. Conclusions: Gene-diet interactions in folate metabolism may contribute to racial disparities in prostate cancer aggressiveness. Higher folate intake may elevate risk among genetically susceptible AA men. These findings highlight the need for ancestry-informed nutrition and cancer prevention strategies tailored to at-risk populations. Citation Format: L. Joseph Su, MinJae Lee, Ping-Ching Hsu. Racial disparities in folate metabolism, genetic variants, and prostate cancer aggressiveness [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A064.