Kibel Adam S, Ahn Jiyoung, Isikbay Masis, Klim Aleksandra, Wu William S, Hayes Richard B, Isaacs William B, Daw E Warwick
Division of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Division of Epidemiology, Department of Environmental Medicine, NYU School of Medicine, New York, New York.
Prostate. 2016 Apr;76(5):479-90. doi: 10.1002/pros.23139. Epub 2015 Dec 28.
Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa.
Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models.
Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups.
This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma.
由于大量前列腺癌（PCa）患者被诊断出患有不太可能造成危害的疾病，与临床侵袭性PCa相关的基因标记具有潜在的临床应用价值。由于细胞周期检查点失调对癌症的发生和发展至关重要，我们检验了细胞周期基因中的常见种系变异与侵袭性PCa相关的假设。
通过两阶段设计，对88个基因中的364个常见序列变异进行了检测。第一阶段包括258例侵袭性PCa患者和442例对照，第二阶段增加了384例侵袭性PCa患者和463例对照。对欧美和非裔美国人样本分别进行分析。在第一阶段，通过Illumina Goldengate检测法对单核苷酸多态性（SNP）进行分型，而在第二阶段，通过焦磷酸测序检测法对SNP进行分型。使用logistic回归分析的加性、显性和隐性模型比较病例组和对照组之间的基因型频率。
在欧美人群中，10个基因（CCNC、CCND3、CCNG1、CCNT2、CDK6、MDM2、SKP2、WEE1、YWHAB、YWHAH）中的11个变异以及在非裔美国人中7个基因（CCNG1、CDK2、CDK5、MDM2、RB1、SMAD3、TERF2）中的9个变异被发现至少在一种模型下与侵袭性PCa相关。特别值得关注的是，CCNC（rs3380812）在来自两个机构的欧美队列中均与风险相关。CDK2（rs1045435）和CDK5（rs2069459）在来自两个机构的非裔美国人队列中均与风险相关。最后，MDM2和CCNG1中的变异在两个种族群体中均对侵袭性PCa具有保护作用。
本研究证实细胞周期基因中的多态性与临床侵袭性PCa相关。有必要在其他人群中验证这些标记，但这些标记可能有助于识别有潜在致命性癌症风险的患者。
