Methylation of Retinoic Acid Receptor, Beta (RARB) Gene Increases Risk for Prostate Cancer in African-American Men

Abstract DNA methylation is an indicator of the initiation of prostate carcinogenesis and as such has utility as a marker of risk in pathologically negative prostate tissue samples. We conducted a matched case-control study nested in a historical cohort of over 6,000 men with pathologically benign prostate specimens identified between January 1991 and November 2002 with no previous history of prostate cancer. Eligible cases were diagnosed with prostate cancer at least one year after cohort entry. Controls were selected through incidence density sampling and matched to cases on date and age at cohort entry, race, and type of specimen. In 310 matched prostate cancer case-control pairs (65% white; 35% African American), we assayed the DNA of the benign prostate specimen for presence of methylation in a five-gene panel (APC, RARB, CCND2, RASSF1, MGMT) and then estimated the risk of developing prostate cancer associated with methylation at each gene for the whole sample and stratified by race. Overall, methylation of RARB had the strongest association with prostate cancer risk (HR = 1.94; 95% CI = 1.30 – 2.91). In race-stratified analyses, the majority of the increased risk associated with RARB was found in the African-American sample (HR = 3.40; 95% CI = 1.68–6.88). In addition, APC was also associated with increased risk for prostate cancer in the African-American sample (HR = 2.17; 95% CI = 1.09–4.29). In a model that included both genes, only RARB remained statistically significantly associated with prostate cancer (HR = 3.14; 95% CI = 1.54–6.44). In whites, methylation was not associated with prostate cancer for any of the five genes assayed. In summary, positive methylation status at RARB and APC in pathologically benign prostate is associated with significant increased risk for subsequent prostate cancer, but primarily in African-American men. Whether this race-specific risk is due to racial differences in environmental stimuli and/or biology is unclear, but further study of DNA methylation in the earliest stages of prostate carcinogenesis may help explain the disproportionate burden of this disease among African-American men.