Germline Sequence Variants and Prostate-Specific Antigen Interpretation

Prostate-specific antigen (PSA)2 is the primary biomarker used to screen for prostate cancer. PSA has limited specificity as a marker, however, and it can be increased in multiple noncancerous conditions [e.g., prostatitis, benign prostatic hyperplasia (BPH)] and after prostatic manipulation (e.g., catheterization) (1, 2).There is now emerging evidence that PSA concentrations may also be affected by genetic variables. Through genome-wide association studies, investigators have identified >30 single-nucleotide polymorphisms (SNPs) that are associated with prostate cancer susceptibility. Eeles et al. reported a strong association of SNPs on chromosomes 10 (rs10993994) and 19 (rs2735839) with PSA concentration and prostate cancer risk (3). It is noteworthy that rs2735839 is located near the KLK3 3 (kallikrein-related peptidase 3) gene on chromosome 19, which encodes PSA, potentially underlying the relationship.In 2009, our group further explored the potential implications of these intriguing findings for prostate cancer screening (4). With 505 men from the Baltimore Longitudinal Study of Aging, we used mixed-effects models to evaluate the relationships between genotype, PSA, and prostate cancer risk. In a model with age and date, there was a 1.18-fold (18%) increased risk ratio for prostate cancer per unit increase in PSA. In an expanded model that also considered the SNP genotypes on chromosomes 10 (rs10993994) and 19 (rs2659056 and rs2735839) and the interaction between genotype and PSA, we found significant differences in prostate cancer risk by PSA that depended on genotype. Specifically, the risk ratio for prostate cancer was …