Dataset Information

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

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.

SUBMITTER: Batra J

PROVIDER: S-EPMC3223160 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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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.

Batra Jyotsna J Lose Felicity F O'Mara Tracy T Marquart Louise L Stephens Carson C Alexander Kimberly K Srinivasan Srilakshmi S Eeles Rosalind A RA Easton Douglas F DF Al Olama Ali Amin AA Kote-Jarai Zsofia Z Guy Michelle M Muir Kenneth K Lophatananon Artitaya A Rahman Aneela A AA Neal David E DE Hamdy Freddie C FC Donovan Jenny L JL Chambers Suzanne S Gardiner Robert A RA Aitken Joanne J Yaxley John J Kedda Mary-Anne MA Clements Judith A JA Spurdle Amanda B AB

PloS one 20111123 11

<h4>Background</h4>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.<h4>Objectives</h4>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 ...[more]

PMID: 22132073

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Project description:Novel biomarkers for prostate cancer (PCa) diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and PCa risk and aggressiveness. A total of 311 Caucasian men (155 controls and 156 patients) were genotyped for 9 SNPs in AR, CYP17A1, LHCGR, ESR1 and ESR2 genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D´Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan-Meier for the association between SNPs and time to biochemical progression. We found 5 variants (CYP17A1) rs743572, rs6162, rs6163; (LHCGR) rs2293275 and (ESR2) rs1256049 that were statistically significant according to clinical variables (PSA, D´Amico risk and T stage) on a case-case analysis. Moreover, the presence of A and G alleles in rs743572 and rs6162 respectively, increase the risk of higher PSA levels (>10 ng/?l). With respect to D´Amico risk rs743572 (AG-GG), rs6162 (AG-AA) and rs6163 (AC-AA) were associated with an increased risk; and last, AC and AA genotypes for rs6163 were associated with a shorter biochemical recurrence free survival (BRFS) in patients with radical prostatectomy. In multigene analysis, several variants in SNPs rs2293275, rs6152, rs1062577, rs6162, rs6163, rs1256049 and rs1004467 were described to be associated with a more aggressiveness in patients. However, none of the selected SNPs show significant values between patients and controls. In conclusion, this study identified inherited variants in genes CYP17A1, LHCGR and ESR2 related to more aggressiveness and/or a poor progression of the disease. According to this study, new promise PCa biomarkers for clinical management could be included in these previous SNPs.

Dataset Information

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

Publications

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

Similar Datasets

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