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Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease

Authors' Affiliations: ¹ Center for Cancer Genomics, ² Center for Human Genomics, and Department of ³ Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁴ Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland; and ⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Requests for reprints: William B. Isaacs, Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287. Phone: 410-955-2518; Fax: 410-955-0833; E-mail: wisaacs{at}jhmi.edu.

Purpose: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain.

Experimental Design: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested.

Results: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening.

Conclusions: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.