Association between Prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data.

Authors:
Jyotsna Batra
Jyotsna Batra
Institute of Health and Biomedical Innovation and School of Biomedical Science
Kelvin Grove | Australia
Felicity Lose
Felicity Lose
Queensland Institute of Medical Research
Australia
Louise Marquart
Louise Marquart
Queensland Institute of Medical Research
Australia
Carson Stephens
Carson Stephens
Queensland University of Technology
Australia
Kimberly Alexander
Kimberly Alexander
School of Nursing
Australia
Srilakshmi Srinivasan
Srilakshmi Srinivasan
Queensland University of Technology
Australia
Rosalind A Eeles
Rosalind A Eeles
The Institute of Cancer Research
United Kingdom

PLoS One 2011 23;6(11):e26527. Epub 2011 Nov 23.

Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

Background: Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease.

Objectives: We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. METHODS AND DATA SOURCES: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study.

Results: Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p<0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77-0.93; p = 2.7×10(-4)). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells.

Conclusions: Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

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Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026527PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223160PMC

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April 2012
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