The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients

Purpose: Gleason score (GS) 7 prostate cancer is a heterogeneous disease with different clinical behavior. We sought to identify genetic biomarkers that may predict the aggressiveness of GS 7 diseases.

Experimental Design: We genotyped 72 prostate cancer susceptibility SNPs identified in genome-wide association studies in 1,827 white men with histologically confirmed prostate adenocarcinoma. SNPs associated with disease aggressiveness were identified by comparing high-aggressive (GS ≥-8) and lowaggressive (GS ≤ 6) cases. The significant SNPs were then tested to see whether they could further stratify GS 7 prostate cancer.

Results: Three SNPs-rs2735839, rs10486567, and rs103294-were associated with biopsy-proven high-aggressive (GS ≥-8) prostate cancer (P < 0.05). Furthermore, the frequency of the variant allele (A) at rs2735839 was significantly higher in patients with biopsy-proven GS 43 disease than in those with GS 3 + 4 disease (P 0.003). In multivariate logistic regression analysis, patients carrying the A allele at rs2735839 exhibited a 1.85-fold (95% confidence interval, 1.31-2.61) increased risk of being GS 4 + 3 compared with those with GS 3 + 4. The rs2735839 is located 600 base pair downstream of the KLK3 gene (encoding PSA) on 19q13.33 and has been shown to modulate PSA level, providing strong biologic plausibility for its association with prostate cancer aggressiveness.

Conclusions: We confirmed the association of the rs2735839 with high-aggressive prostate cancer (GS ≥-8). Moreover, we reported for the first time that rs2735839 can stratify GS 7 patients, which would be clinically important for more accurately assessing the clinical behavior of the intermediate-grade prostate cancer and for tailoring personalized treatment and posttreatment management.