Abstract A9: Genetic polymorphisms in the vitamin D receptor gene and androgen pathway gene SRD5A2 may be informative of prostate cancer risk in African American men undergoing prostate cancer screening

Abstract

Abstract Background: Men with a family history (FH) of prostate cancer (PCA) and African American (AA) men are at 2 to 7-fold increased risk for the disease. Assessing risk for PCA in these high-risk men has been challenging due to the lack of available genetic testing. The vitamin D and androgen pathways have been studied for years for association to prostate cancer risk with single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene and genes encoding enzymes involved in testosterone biosynthesis found to have no substantial association to prostate cancer risk. However, a recent study found an interaction between the FokI SNP in VDR and the V89L SNP in SRD5A2 (converts testosterone to dihydrotestosterone) in non-Hispanic white men. In addition, in Hispanic white men, the V89L SRD5A2 polymorphism and the CDX2 VDR SNP was associated with prostate cancer. We evaluated these particular genetic variants in VDR and SRD5A2 for association to prostate cancer and time to prostate cancer diagnosis in high-risk men enrolled in the Prostate Cancer Risk Assessment Program (PRAP)- a screening and research program with 60% African American participation. Methods: Eligibility for PRAP includes men ages 35–69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, or men with BRCA1/2 mutations. Current criteria for biopsy include PSA > 2.0 ng/mL, PSA 1.5–2.0 ng/mL with free PSA < 25%, any abnormality on digital rectal examination, or PSA velocity of 0.75 ng/mL/year. All biopsies are 12-core under transrectal ultrasound guidance with additional cores taken at physician discretion. Genotyping of SRD5A2 V89L and VDR CDX2 was performed using the Taqman® SNP Genotyping Assay (Applied Biosystems) per manufacturer's instructions. Pyrosequencing methods were used for the FokI SNP in VDR as Taqman assays did not produce reliable results. Standard statistical methods were used to determine allele and genotype distributions by race. Cox models were used to determine time to PCA diagnosis. Results: 661 PRAP men had genotype data available for FokI and V89L, while 380 men had genotype data for CDX2 and V89L. Among 236 AA men with at least one follow-up visit included in the FokI-V89L analysis, a significant interaction was seen between FokI and V89L genotypes after adjusting for age and PSA at entry (p=0.01). Hazard ratio estimates for AA men with the FokI CC genotype and V89L LV/LL genotypes vs. VV was 2.51 (95% CI 1.07–5.90). No interaction was seen between FokI and V89L genotypes among 194 Caucasian men, where FokI genotype alone was found to have a significant association to PCA (Hazard Ratio for FokI TT/CT vs CC = 0.29, 95% CI 0.14–0.62). No significant association to PCA was seen for CDX2 either alone or in combination with V89L for AA and Caucasian men in this analysis. Conclusions: FokI CC in VDR and V89L LV/LL in SRD5A2 appear to be informative of time to PCA diagnosis and risk for PCA in AA men undergoing PCA screening. FokI TT/CT genotype appears to have a protective effect in Caucasian men for PCA. Further study is warranted. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A9.