. (2011) Association between Prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data. PLoS ONE, Vol.6 (No.11). e26527. ISSN 1932-6203

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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.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Prostate -- Cancer -- Susceptibility, Prostate -- Cancer -- Genetic aspects, Prostate -- Cancer -- Etiology
Journal or Publication Title:	PLoS ONE
Publisher:	Public Library of Science
ISSN:	1932-6203
Date:	23 November 2011
Volume:	Vol.6
Number:	No.11
Page Range:	e26527
Identification Number:	10.1371/journal.pone.0026527
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	National Health and Medical Research Council (Australia) (NHMRC), Prostate Cancer Foundation of Australia (PCFA), Queensland University of Technology. Institute of Health and Biomedical Innovation (IHBI), Australia, Queensland, Cancer Council Queensland, Cancer Research UK (CRUK), Institute of Cancer Research: Royal Cancer Hospital, Prostate Action, National Cancer Research Institute (NCRI), Great Britain. National Health Service (NHS), NHS R & D HTA Programme (Great Britain) (HTA), Great Britain. Dept. of Health (DoH), Medical Research Council (Great Britain) (MRC), South West Regional Health Authority (Great Britain), National Institute for Health Research (Great Britain) (NIHR)
Grant number:	390130 (NHMRC), 290456 (NHMRC), 614296 (NHMRC), 1009458 (NHMRC), PG7 (PCFA), C5047/A3354 (CRUK), 96/20/06 (NHS), 96/20/99 (NHS), C522/A8649 (CRUK), G0500966 (MRC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/40145

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