Assessing the clinical role of genetic markers of early-onset prostate cancer among high-risk men enrolled in prostate cancer early detection

Abstract

Background: Men with familial prostate cancer and African American men are at risk for developing prostate cancer at younger ages. Genetic markers predicting early-onset prostate cancer may provide clinically useful information to guide screening strategies for high-risk men. We evaluated clinical information from six polymorphisms associated with early-onset prostate cancer in a longitudinal cohort of high-risk men enrolled in prostate cancer early detection with significant African American participation.

Methods: Eligibility criteria include ages 35 to 69 with a family history of prostate cancer or African American race. Participants undergo screening and biopsy per study criteria. Six markers associated with early-onset prostate cancer [rs2171492 (7q32), rs6983561 (8q24), rs10993994 (10q11), rs4430796 (17q12), rs1799950 (17q21), and rs266849 (19q13)] were genotyped. Cox models were used to evaluate time to prostate cancer diagnosis and prostate-specific antigen (PSA) prediction for prostate cancer by genotype. Harrell's concordance index was used to evaluate predictive accuracy for prostate cancer by PSA and genetic markers.

Results: Four hundred and sixty participants with complete data and ≥ 1 follow-up visit were included. Fifty-six percent were African American. Among African American men, rs6983561 genotype was significantly associated with earlier time to prostate cancer diagnosis (P = 0.005) and influenced prediction for prostate cancer by the PSA (P < 0.001). When combined with PSA, rs6983561 improved predictive accuracy for prostate cancer compared with PSA alone among African American men (PSA = 0.57 vs. PSA + rs6983561 = 0.75, P = 0.03).

Conclusions: Early-onset marker rs6983561 adds potentially useful clinical information for African American men undergoing prostate cancer risk assessment. Further study is warranted to validate these findings.

Impact: Genetic markers of early-onset prostate cancer have potential to refine and personalize prostate cancer early detection for high-risk men.

Figure 1

Time to PCA Diagnosis by rs6983561 Genotype

Figure 2. Race-Specific Three-Year Prediction for Prostate Cancer by PSA at Entry into PRAP by rs6983561 Genotype

3-year prediction for prostate cancer was computed from Cox models where the covariates included the cubic spline of age and PSA at baseline. Probabilities were computed using STATA 10.0. Participant specific predictions were computed based on their individual characteristics (age and baseline PSA) and fitted model coefficient. Each participant that was used in the analysis received a unique prediction. Prostate cancer cases diagnosed within 6 months of enrollment into PRAP were excluded (n=42 cases excluded).