Evaluation of Multiple Risk–Associated Single Nucleotide Polymorphisms Versus Prostate-Specific Antigen at Baseline to Predict Prostate Cancer in Unscreened Men

Abstract 

Background

Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear.

Objective

Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men.

Design, setting, and participants

This study used a nested case-control design based on the Malmö Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005.

Measurements

We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer.

Results and limitations

Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p<0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage ≥T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage ≥T3, metastasis, Gleason score ≥8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group.

Conclusions

Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmö, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline.

Take Home Message 

Although numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer risk have been identified and can be consistently replicated, these SNPs neither can predict who will develop prostate cancer alone nor do they enhance the predictive power of prostate-specific antigen testing.

Keywords: Prostate cancer, Biomarkers, SNPs, PSA, Sensitivity and specificity