Panagiotou Orestis A, Travis Ruth C, Campa Daniele, Berndt Sonja I, Lindstrom Sara, Kraft Peter, Schumacher Fredrick R, Siddiq Afshan, Papatheodorou Stefania I, Stanford Janet L, Albanes Demetrius, Virtamo Jarmo, Weinstein Stephanie J, Diver W Ryan, Gapstur Susan M, Stevens Victoria L, Boeing Heiner, Bueno-de-Mesquita H Bas, Barricarte Gurrea Aurelio, Kaaks Rudolf, Khaw Kay-Tee, Krogh Vittorio, Overvad Kim, Riboli Elio, Trichopoulos Dimitrios, Giovannucci Edward, Stampfer Meir, Haiman Christopher, Henderson Brian, Le Marchand Loic, Gaziano J Michael, Hunter David J, Koutros Stella, Yeager Meredith, Hoover Robert N, Chanock Stephen J, Wacholder Sholom, Key Timothy J, Tsilidis Konstantinos K
Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Eur Urol. 2015 Apr;67(4):649-57. doi: 10.1016/j.eururo.2014.09.020. Epub 2014 Sep 30.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
在全基因组关联研究（GWAS）中尚未发现侵袭性前列腺癌特有的单核苷酸多态性（SNP）。
测试与其他性状相关的SNP是否也会影响侵袭性前列腺癌的风险。
设计、设置和参与者：通过已发表的GWAS目录识别出与前列腺癌以外的任何表型相关的SNP（p≤10⁻⁷），并在来自乳腺癌和前列腺癌队列联盟（BPC3）的2891例侵袭性前列腺癌病例和4592例对照中进行测试。对40个最显著的SNP在来自前列腺癌关联基因组癌症相关改变研究组（PRACTICAL）联盟的4872例侵袭性前列腺癌病例和24534例对照中进行随访。
估计侵袭性前列腺癌的优势比（OR）和95%置信区间（CI）。
BPC3共评估了4666个SNP。在已报道的前列腺癌风险区域发现了两个信号。8q24.21处的rs7014346在BPC3试验中与侵袭性前列腺癌存在边缘关联（p = 1.6×10⁻⁶），而在PRACTICAL进行荟萃分析后，汇总OR为1.21（95% CI 1.16 - 1.27；p = 3.22×10⁻¹⁸）。17q24.3处的rs9900242在荟萃分析中也与侵袭性疾病存在边缘关联（OR 0.90，95% CI 0.86 - 0.94；p = 2.5×10⁻⁶）。当以相关的已知前列腺癌SNP为条件时，这两个SNP均不再具有统计学显著性。BPC3和PRACTICAL的荟萃分析确定了第三个有前景的信号，以2q34处的rs16844874为标志，独立于已知的前列腺癌基因座（OR 1.12，95% CI 1.06 - 1.19；p = 4.67×10⁻⁵）；已表明与该信号相关的SNP会影响甘氨酸浓度。主要局限性是BPC3和PRACTICAL之间侵袭性前列腺癌定义的异质性。
我们未识别出侵袭性前列腺癌的新SNP。然而，rs16844874可能为甘氨酸途径在前列腺癌病因学中的作用提供初步的遗传证据。
我们评估了与多种性状相关的基因变异是否与侵袭性前列腺癌的风险相关。未识别出新的此类变异。
