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Variants of the hK2 Protein Gene (KLK2) Are Associated with Serum hK2 Levels and Predict the Presence of Prostate Cancer at Biopsy

Authors' Affiliations: ¹ Division of Urology; Departments of ² Pathology and ³ Radiation Oncology, Sunnybrook Health Sciences Centre; ⁴ Division of Urology; Departments of ⁵ Pathology and ⁶ Medical Imaging, University Health Network; ⁷ Department of Medicine, Immunology, and Medical Genetics and Microbiology, Mount Sinai Hospital; and ⁸ Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Robert K. Nam, Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, MG-406, Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-5075; Fax: 416-480-6121; E-mail: robert.nam{at}utoronto.ca.

Purpose: Increased levels of serum human kallikrein-2 (hK2) and an hK2 gene (KLK2) variant are positively associated for prostate cancer, but the relationships between them remain unclear. We examined five variants of the KLK2 gene to further define its relevance to prostate cancer susceptibility and hK2 levels.

Experimental Design: We genotyped 645 men with biopsy-proven prostate cancer (cases) and 606 males with biopsies negative for prostate cancer (controls) for five additional single nucleotide polymorphisms (SNP) across the KLK2 gene and also tested for serum hK2 levels. These SNPs were identified from sequencing the KLK2 gene among 20 patients with aggressive prostate cancer. Odds ratios (OR) for prostate cancer detection and haplotype analysis were done.

Results: Among the SNPs studied, the A allele of the KLK2-SNP1 (G > A, rs2664155) and the T allele of the KLK2-SNP5 (C > T, rs198977) polymorphisms showed positive associations with prostate cancer, adjusted ORs for KLK2-SNP1 AG and AA genotypes being 1.4 [95% confidence interval (95% CI), 1.2-1.8; P = 0.002] and for KLK2-SNP5 TT or CT genotypes being 1.3 (95% CI, 1.1-1.6; P = 0.05). Haplotype analyses also revealed a significant association between prostate cancer and the haplotype containing both risk alleles (ACCTT), OR being 5.1 (95% CI, 1.6-6.5; P = 0.005). Analysis of serum hK2 revealed hK2 levels to be significantly increased in association with KLK2-SNP1 AA and AG risk genotypes compared with the GG genotype (P = 0.001) and also in association with the ACCTT risk haplotype compared with the most common non-risk haplotype (P = 0.05).

Conclusions: These findings suggest a role for the KLK2 gene in prostate cancer susceptibility and imply that this role may be realized at least in part by the induction of increases in hK2 production.