The identification of prostate cancer susceptible gene by whole genome search and candidate gene approach

前言与目的：遗传多态性可能影响前列腺癌（Pca）的易感性。通过连锁分析，从美国的家族病例中鉴定出HPC2/ELAC2基因。HER-2基因是原癌基因，编码跨膜酪氨酸激酶受体，在包括前列腺癌在内的许多人类癌症中起重要作用。为了确定HPC/ELAC2和HER2基因与日本Pca的关系，我们分析了这两个基因在散发性Pca患者和匹配对照中多态性位点的频率。方法：对日本散发性Pca患者（n=285）和匹配对照（n=233）进行HPC/ELAC2基因的Ser257Leu和Ala541Thr基因分型，HER-2基因的Ile655Val基因分型。对照组为无癌史的日本男性，包括前列腺癌和正常PSA水平（低于4.0ng/m1）。统计学分析采用Fisher精确检验和logistic回归分析。结果：我们观察到Pca患者HPC/ELAC2基因Thr541的频率（8.4%）显著高于对照组（2.1%）（p=0.0030，优势比(OR) = 4.02）。HER-2基因中Va1655在Pca中的表达频率也显著降低（癌组14.7%，对照组26.2%,p=0.0025， OR=0.476）。结论：我们的研究结果表明，HPC/ELAC2中Thr541在日本散发性Pca易感性中具有显著意义（OR =4.02）。Thr 541多态性在美国首次被报道与家族性Pca有关。在我们的分析中，在日本的散发病例中也观察到类似的现象。而在日本的Pca患者中，HER2中Va1655的频率明显较低。此前有报道称，该Va1655Val在乳腺癌患者中出现的频率明显更高。前列腺癌和乳腺癌之间的相反观察结果可能受到这两种癌症的激素环境的影响。

Introduction and Objective : The genetic polymorphisms may affect the of prostate cancer (Pca) susceptibility. HPC2/ELAC2 gene was identified by linkage analysis from familial cases in USA. While, HER-2 gene is a proto-oncogene, encoding a transmembrane tyrosine kinase receptor that has an important role in many human cancers including Pca. To determine the association of HPC/ELAC2 and HER2 gene with Japanese Pca, we analyzed the frequency of polymorphic sites of these two genes in sporadic Pca patients and matched controls.Methods : We genotyped at Ser257Leu and Ala541Thr in HPC/ELAC2 gene, and at Ile655Val in HER-2 gene in sporadic Japanese Pca patients (n=285) and matched controls (n=233). Controls were unrelated Japanese men who had no history of cancer including Pca and normal PSA level (less than 4.0ng/m1). Statistical analyses were performed by Fisher's exact test and logistic regression analysis.Results : We observed a significantly higher frequency of the Thr541 in HPC/ELAC2 gene in Pca patients (8.4%) compared to the control group (2.1%) (p=0.0030, Odds Ratio (OR) = 4.02). Also Va1655 in HER-2 gene was significantly lower frequency in Pca (14.7 % in cancer vs. 26.2 % in control, p=0.0025, OR=0.476).Conclusions : Our results indicate that Thr541 in HPC/ELAC2 has a significance (OR =4.02) in the predisposition of sporadic Pca in Japan. The Thr 541 polymorphism was first reported to link to familial Pca in USA. In our analyses, similar phenomenon was observed in sporadic cases in Japan. While, the frequency of Va1655 in HER2 was significantly lower in Pca patients in Japan. This Va1655Val was previously reported that significant higher frequency was observed in breast cancer patients. This opposite observation between Pca and breast cancer may be affected by hormonal environment of these two cancers.