Potential clinical utilities of prostate cancer risk-associated SNPs

Abstract

Abstract Prostate cancer (PCa) is the most common solid organ malignancy affecting American men and the second leading cause of cancer related death. Recently, more than 30 PCa risk-associated single nucleotide polymorphisms (SNPs) have been discovered from genome-wide association studies (GWAS). These risk-associated SNPs have been consistently replicated in multiple case-control study populations of European descent. Although each of these SNPs is only moderately associated with PCa risk, a genetic score based on a combination of risk-associated SNPs can be used to identify men at high risk for PCa. However, these results were obtained from case-control studies which have several significant limitations. The validity of these genetic associations, the relative performance of genetic markers for PCa risk prediction compared to existing clinical variables such as PSA, and more importantly, whether genetic markers add value to existing clinical variables, are key questions that need to be addressed in well-controlled prospective studies prior to their consideration for clinical use. In this presentation, I will present the findings of PCa risk prediction using multiple risk-associated SNPs. I will also discuss our effort to assess clinical validity and clinical utility of these genetic markers in the Reduction by DUtasteride of Prostate Cancer Events (REDUCE) study, a large randomized clinical trial. All men in the REDUCE trial had a negative biopsy at baseline and were followed-up for four years, with scheduled not-for-cause (i.e. regardless of PSA levels and other clinical indications) prostate biopsies at years 2 and 4. Therefore, this study design minimizes the potential impact of PSA detection bias on associations between PCa risk and SNPs. In addition, because it is a clinical trial, a number of clinical variables, such as free/total PSA ratio and prostate volume were measured at baseline using a standardized protocol. Therefore, it allows us to compare performance of genetic markers and existing clinical variables in predicting positive prostate biopsy in the same study. Finally, the study design allows us to assess whether genomic-targeted chemoprevention, based on estimated risk from genetic markers, can improve efficacy of chemoprevention. This study represents an important next and critical step towards an assessment of the potential clinical utility of genetic markers.