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Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

ABSTRACT: BACKGROUND:Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging. OBJECTIVE:To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer. DESIGN, SETTING, AND PARTICIPANTS:Blood 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 ANALYSIS:A 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 LIMITATIONS:We 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. CONCLUSIONS:The 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 SUMMARY:We identify two genetic markers that are associated with prostate-cancer-specific survival time.

SUBMITTER: Li W

PROVIDER: S-EPMC6287611 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

Li Weiqiang W Middha Mridu M Bicak Mesude M Sjoberg Daniel D DD Vertosick Emily E Dahlin Anders A Häggström Christel C Hallmans Göran G Rönn Ann-Charlotte AC Stattin Pär P Melander Olle O Ulmert David D Lilja Hans H Klein Robert J RJ

European urology 20180707 6

<h4>Background</h4>Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.<h4>Objective</h4>To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.<h4>Design, setting, and participants</h4>Blood 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 a ...[more]

PMID: 30289108

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Project description:BackgroundNo single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).ObjectiveTo test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.Design, setting, and participantsSNPs 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.Outcome measurements and statistical analysisOdds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated.Results and limitationsA 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.ConclusionsWe 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.Patient summaryWe evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

Dataset Information

Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

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Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

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