Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.
Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.
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DOI：
10.1016/j.eururo.2018.06.021
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发表时间：
2018-12
期刊：
影响因子：
23.4
通讯作者：
Klein RJ
中科院分区：
文献类型：
--
作者：
Li W;Middha M;Bicak M;Sjoberg DD;Vertosick E;Dahlin A;Häggström C;Hallmans G;Rönn AC;Stattin P;Melander O;Ulmert D;Lilja H;Klein RJ
大多数被诊断患有前列腺癌的男性患癌症的风险较低。如何在诊断时预测前列腺癌的进展仍然具有挑战性。确定与前列腺癌死亡相关的单核苷酸多态性（SNPs）。1991-1996年期间，在瑞典收集了11 506名男子的血液样本。其中，1053名男性被诊断患有前列腺癌，245人死于这种疾病。获得诊断时的分期和分级以及结果信息，并对所有病例的DNA进行基因分型。使用考克斯比例风险模型测试6，126，633个SNP与前列腺癌特异性存活时间的关联，校正诊断时的年龄和诊断时的分期和等级。1×10 - 6被用作提示性显著性阈值。使用表达数量性状基因座（eQTL）分析检测阳性候选SNP与基因表达的关联。我们在7个独立位点发现了12个与前列腺癌特异性生存时间相关的SNP。在检测的6，126，633个SNP中，有一个达到了全基因组显著性（p < 5×10−8），并在一个独立队列中重复：AOX 1基因中的rs73055188（p = 5.27×10−9，每个等位基因HR = 2.27，95% CI 1.72-2.98）。第二个SNP达到了提示的显著性水平（p < 1×10−6），并在一个独立队列中复制：SMG 7基因中的rs 2702185（p = 7.1×10−7，每个等位基因HR = 2.55，95% CI = 1.76-3.69）。rs73055188与AOX 1表达水平相关，AOX 1表达水平与独立队列中前列腺癌的生化复发相关。这种关联在其他族裔群体中尚待证实。AOX 1基因座rs73055188与前列腺癌特异性生存时间相关，AOX 1基因表达水平与前列腺癌生化复发相关。我们确定了两个与前列腺癌特异性生存时间相关的遗传标记。
Most men diagnosed with prostate cancer have low risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging. To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer. 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 was obtained and DNA from all cases was genotyped. 6,126,633 SNPs were tested for association with prostate cancer specific survival time using a Cox proportional hazards model, adjusted for age at diagnosis and stage and grade at diagnosis. 1×10−6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait loci (eQTLs) analysis. 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 HR = 2.27, 95% 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. 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. 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. We identify two genetic markers that are associated with prostate cancer specific survival time.
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