Duggan David, Zheng Siqun L, Knowlton Michele, Benitez Debbie, Dimitrov Latchezar, Wiklund Fredrik, Robbins Christiane, Isaacs Sarah D, Cheng Yu, Li Ge, Sun Jielin, Chang Bao-Li, Marovich Leslie, Wiley Kathleen E, Bälter Katarina, Stattin Pär, Adami Hans-Olov, Gielzak Marta, Yan Guifang, Sauvageot Jurga, Liu Wennuan, Kim Jin Woo, Bleecker Eugene R, Meyers Deborah A, Trock Bruce J, Partin Alan W, Walsh Patrick C, Isaacs William B, Grönberg Henrik, Xu Jianfeng, Carpten John D
Division of Genetic Basis of Human Disease, Translational Genomics Research Institute, Phoenix, AZ, USA.
J Natl Cancer Inst. 2007 Dec 19;99(24):1836-44. doi: 10.1093/jnci/djm250. Epub 2007 Dec 11.
The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment.
We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study.
Among the approximately 60,000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02).
A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.
对前列腺癌遗传易感性的一致研究结果表明，存在一些种系序列变异使个体易患此病。这些变异可能在筛查和治疗中有用。
我们在498例侵袭性前列腺癌男性患者和494例对照受试者中进行了一项探索性全基因组关联扫描，这些受试者选自瑞典一项基于人群的病例对照研究。我们将该扫描结果与公开可用的癌症遗传易感性标记（CGEMS）研究中侵袭性前列腺癌的结果相结合。基于双侧等位基因检验显示与侵袭性前列腺癌风险有统计学显著关联的单核苷酸多态性（SNP），在两个由欧洲或非裔美国人后裔个体组成的独立研究人群中，使用单侧检验以及与探索性研究中最低值相关的遗传模型（显性或加性），测试其与侵袭性前列腺癌的关联。
在我们的研究和CGEMS共有的约60,000个SNP中，我们鉴定出7个在两项研究中与侵袭性前列腺癌风险有相似（正向或负向）且统计学显著（P<0.01）的关联。对这些SNP在1032例欧洲裔前列腺癌患者和571例对照受试者中的分布分析表明，位于DAB2IP基因的一个SNP，rs1571801，与侵袭性前列腺癌相关，该基因编码一种新型Ras GTP酶激活蛋白和假定的前列腺肿瘤抑制因子（单侧P值 = 0.004）。在一个包括210例前列腺癌患者和346例对照受试者的非裔美国人研究人群中，该关联也具有统计学显著性（单侧P值 = 0.02）。
DAB2IP基因中的一个遗传变异可能与侵袭性前列腺癌风险相关，应进一步评估。
