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

Batra, Jyotsna, Lose, Felicity, O'Mara, Tracy, Marquart, Louise, Stephens, Carson, Alexander, Kimberly, Srinivasan, Srilakshmi, Eeles, Rosalind, Easton, Douglas, Olama, Ali Amin Al, Kote-Jarai, Zsofia, Guy, Michelle, Muir, Ken, Lophatananon, Artitaya, Rahman, Aneela, Neal, David, Hamdy, Freddie, Donovan, Jenny, Chambers, Suzanne, Gardiner, Robert, Aitken, Joanne, Yaxley, John, Kedda, Mary-Anne, Clements, Judith, & Spurdle, Amanda (2011) Association between prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data. PLoS ONE, 6(11), pp. 1-8.

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Abstract

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 = 2.7610 24). 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.

Impact and interest:

6 citations in Scopus
7 citations in Web of Science®
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ID Code: 52093
Item Type: Journal Article
Refereed: Yes
DOI: 10.1371/journal.pone.0026527
ISSN: 1932-6203
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Funding:
Copyright Owner: Copyright 2011 the authors
Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Deposited On: 19 Jul 2012 06:27
Last Modified: 09 Apr 2014 12:21

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