A Genetic Variant Near Klk3 Gene Is Associated With Aggressive Prostate Cancer And Can Stratify Gleason Score 7 Patients

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Purpose: Gleason score (GS) 7 prostate cancer is a heterogeneous disease with significant differences in aggressiveness and prognosis. We sought to identify genetic biomarkers that may predict the aggressiveness of GS 7 diseases. Experimental Design: We genotyped 72 prostate cancer susceptibility single nucleotide polymorphisms (SNPs) identified in genome-wide association studies in 1827 white men with histologically confirmed prostate adenocarcinoma. SNPs associated with disease aggressiveness were identified by comparing high-aggressive (GS ≥8) and low-aggressive (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). Rs2735839 and rs10486567 were also associated with high D'Amico risk groups. Furthermore, the frequency of the variant allele (A) at rs2735839 was significantly higher in patients with biopsy-proven GS 4+3 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% 1.31-2.61) increased risk of being GS 4+3 compared to those with GS 3+4. Rs2735839 is located 600 base pair downstream of KLK3 gene (encoding PSA) on 19q13.33 and has been shown to modulate PSA level, providing strong biological plausibility for its association with prostate cancer aggressiveness. Conclusions: We showed 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 post-treatment management. Citation Format: Jian Gu, Yonggang He, Sara S. Strom, Christopher J. Logothetis, Jeri Kim, Xifeng Wu. A genetic variant near KLK3 gene is associated with aggressive prostate cancer and can stratify Gleason score 7 patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5547. doi:10.1158/1538-7445.AM2014-5547