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A genome-wide pleiotropy scan for prostate cancer risk.

ABSTRACT: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.SNPs implicated in any phenotype other than prostate cancer (p?10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated.A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL.We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology.We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

SUBMITTER: Panagiotou OA

PROVIDER: S-EPMC4359641 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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A genome-wide pleiotropy scan for prostate cancer risk.

Panagiotou Orestis A OA Travis Ruth C RC Campa Daniele D Berndt Sonja I SI Lindstrom Sara S Kraft Peter P Schumacher Fredrick R FR Siddiq Afshan A Papatheodorou Stefania I SI Stanford Janet L JL Albanes Demetrius D Virtamo Jarmo J Weinstein Stephanie J SJ Diver W Ryan WR Gapstur Susan M SM Stevens Victoria L VL Boeing Heiner H Bueno-de-Mesquita H Bas HB Barricarte Gurrea Aurelio A Kaaks Rudolf R Khaw Kay-Tee KT Krogh Vittorio V Overvad Kim K Riboli Elio E Trichopoulos Dimitrios D Giovannucci Edward E Stampfer Meir M Haiman Christopher C Henderson Brian B Le Marchand Loic L Gaziano J Michael JM Hunter David J DJ Koutros Stella S Yeager Meredith M Hoover Robert N RN Chanock Stephen J SJ Wacholder Sholom S Key Timothy J TJ Tsilidis Konstantinos K KK

European urology 20140930 4

<h4>Background</h4>No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).<h4>Objective</h4>To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.<h4>Design, setting, and participants</h4>SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases ...[more]

PMID: 25277271

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Project description:BackgroundMost men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.ObjectiveTo identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.Design, setting, and participantsBlood samples from 11 506 men in Sweden were collected during 1991-1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped.Outcome measurements and statistical analysisA total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1×10-6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis.Results and limitationsWe found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p<5×10-8) and replicated in an independent cohort: rs73055188 (p=5.27×10-9, per-allele hazard ratio [HR]=2.27, 95% confidence interval [CI] 1.72-2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p<1×10-6) and replicated in an independent cohort: rs2702185 (p=7.1×10-7, per-allele HR=2.55, 95% CI=1.76-3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups.ConclusionsThe SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer.Patient summaryWe identify two genetic markers that are associated with prostate-cancer-specific survival time.

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A genome-wide pleiotropy scan for prostate cancer risk.

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A genome-wide pleiotropy scan for prostate cancer risk.

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