Introduction: Prostate Cancer (PCa) disproportionately affects African Americans, as AA men are more commonly diagnosed with aggressive PCa and twice as likely to have mortality from the disease compared to European Americans (EA). The one- carbon metabolism pathway has been extensively studied for cancer development, yet little research has been reported on its association with aggressiveness of cancer at diagnosis. The purpose of our study is to determine whether there is difference by race for the impact of a DHFR 19bp polymorphism together with multiple single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes on a cohort of men diagnosed with either low-aggressive or high-aggressive PCa. Methods: DNA samples from a population-based study of 1,498 PCa subjects in the North Carolina- Louisiana Prostate Cancer Project were analyzed. The DHFR 19bp polymorphism was targeted by utilizing two TaqMan TAMRA probes, one with a FAM fluorescent probe to identify the insertion allele and one with a VIC fluorescent probe to identify the deletion allele. Six SNPs were genotyped via TaqMan SNP genotyping assays by Applied Biosystems. Chi-Square analyses were performed to examine differences in genotype between race. A multivariable logistic regression model adjusted for confounders was utilized to estimate the association of the 19bp DHFR polymorphism and one-carbon metabolism SNPs with PCa aggressiveness. Results: A total of 152 participants were excluded due to insufficient DNA samples, resulting in a sample of 1,346 participants. The analysis consisted of 993 low-aggressive and 345 high aggressive PCa cases. Chi-square analyses revealed significant frequency differences between AAs and EAs for the 19bp DHFR deletion polymorphism (31.2% vs 17.6%), as well as MTHFR rs1801131, MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, and MTHFD2 rs7587117 (P values < 0.0001). After adjusting for confounders, the cohort was stratified based on DHFR polymorphism status. Among subjects with the 19bp DHFR double deletion, individuals with heterozygous MTR rs1805087 (AG) were significantly less likely to have aggressive PCa (OR = 0.27 [0.10, 0.74]) when compared to individuals with the GG genotype. Among the group that had at least one copy of wild-type DHFR, heterozygous individuals (GA) at MTHFD1 rs2236225 had a significantly lower chance of aggressive PCa diagnosis (OR = 0.60 [0.38, 0.95]) compared to individuals with the AA genotype. Conclusion: Substantial differences exist between AAs and EAs in regard to polymorphisms within the one-carbon metabolism pathway. There appears to be significant interaction among genes involved that can be attributable to the racial distribution of genetic polymorphisms. Studies examining the association between folate metabolism and PCa should consider the modulation effect of gene-gene interaction when analyzing the polymorphisms collectively.

Citation Format: C. Tyler Ratliff, Lora J. Rogers, L. Joseph Su. Racial differences in the association of one-carbon metabolism polymorphisms and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-161.