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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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Title
Association between prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in australia and a meta-analysis of GWAS data
Author/Creator
Batra, J
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Lose, Felicity
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O'Mara, T
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Marquart, L
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Stephens, C
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Alexander, K
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Srinivasan, S
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Eeles, R A
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Easton, D F
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Al Olama, A A
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Kote-Jarai, Z
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Guy, M
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Muir, K
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Lophatananon, A
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Rahman, A A
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Neal, D E
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Hamdy, F C
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Donovan, J L
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Chambers, S
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Gardiner, R A
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Aitken, J
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Yaxley, J
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Kedda, M A
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Clements, J A
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Spurdle, A B
Description
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.
Relation
PL o S One / Vol. 6, No. 11
Relation
http://dx.doi.org/10.1371/journal.pone.0026527
Year
2011
Publisher
Public Library of Science
Subject
FoR multidisciplinary
Resource Type
Journal Article
Identifier
ISSN: 1932-6203
Rights
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.
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© 2012 University of the Sunshine Coast, Queensland, Australia | ABN 28 441 859 157 | CRICOS Provider No. 01595D