Variants of the hK2 protein gene (KLK2) are associated with serum hK2 levels and predict the presence of prostate cancer at biopsy.
OBJECTIVE
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.


METHODS
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.
Nam
Robert K
RK
Division of Urology; Department of Pathology, Sunnybrook Health Sciences Centre, University Health Network, Mount Sinai Hospital, University of Toronto, Ontario, Canada. robert.nam@utoronto.ca
Zhang
William W
WW
Klotz
Laurence H
LH
Trachtenberg
John
J
Jewett
Michael A S
MA
Sweet
Joan
J
Toi
Ants
A
Teahan
Seamus
S
Venkateswaran
Vasundara
V
Sugar
Linda
L
Loblaw
Andrew
A
Siminovitch
Kathy
K
Narod
Steven A
SA
D000230:Adenocarcinoma / Q000097:blood*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D001706:Biopsy; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000097:blood*; D020840:Tissue Kallikreins / Q000097:blood* / Q000235:genetics*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D020840:Tissue Kallikreins