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

J Batra; Felicity Lose; T O'Mara; L Marquart; C Stephens; K Alexander; S Srinivasan; R A Eeles; D F Easton; A A Al Olama; Z Kote-Jarai; M Guy; K Muir; A Lophatananon; A A Rahman; D E Neal; F C Hamdy; Jenny L Donovan; S Chambers; R A Gardiner; J Aitken; J Yaxley; M A Kedda; J A Clements; A B Spurdle

doi:10.1371/journal.pone.0026527

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

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

J Batra, Felicity Lose, T O'Mara, L Marquart, C Stephens, K Alexander, S Srinivasan, R A Eeles, D F Easton, A A Al Olama, …

PLoS One, Vol.6(11)

2011

DOI: https://doi.org/10.1371/journal.pone.0026527

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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 = 2.7×10 -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. © 2011 Batra et al. 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.

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Title: Association between prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in australia and a meta-analysis of GWAS data
Authors: J Batra (Author) - Queensland University of Technology
Felicity Lose (Author) - Queensland Institute of Medical Research
T O'Mara (Author) - Queensland Institute of Medical Research
L Marquart (Author) - Queensland Institute of Medical Research
C Stephens (Author) - Queensland University of Technology
K Alexander (Author) - Queensland University of Technology
S Srinivasan (Author) - Queensland University of Technology
R A Eeles (Author) - Institute of Cancer Research & Cancer Genetics Unit, United Kingdom
D F Easton (Author) - Queensland University of Technology
A A Al Olama (Author) - Queensland University of Technology
Z Kote-Jarai (Author) - Institute of Cancer Research & Cancer Genetics Unit, United Kingdom
M Guy (Author) - Institute of Cancer Research & Cancer Genetics Unit, United Kingdom
K Muir (Author) - Warwick University, United Kingdom
A Lophatananon (Author) - Warwick University, United Kingdom
A A Rahman (Author) - University of Nottingham, United Kingdom
D E Neal (Author) - University of Cambridge, United Kingdom
F C Hamdy (Author) - John Radcliffe Hospital, United Kingdom
Jenny L Donovan (Author)
S Chambers (Author) - Griffith University
R A Gardiner (Author) - University of Queensland
J Aitken (Author) - Cancer Council Queensland
J Yaxley (Author) - Brisbane Private Hospital
M A Kedda (Author) - Queensland University of Technology
J A Clements (Author) - Queensland University of Technology
A B Spurdle (Author) - Queensland Institute of Medical Research
Publication details: PLoS One, Vol.6(11)
Publisher: Public Library of Science
Date published: 2011
DOI: 10.1371/journal.pone.0026527
ISSN: 1932-6203
Copyright note: Copyright © 2011 Batra et al. 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.
Organisation Unit: University of the Sunshine Coast, Queensland; Office of Research
Language: English
Record Identifier: 99451034202621
Output Type: Journal article

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