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

前言与目的：基因多态性可能影响前列腺癌(Pca)的易感性。对美国家族性病例的HPC2/ELAC2基因进行连锁分析。而HER-2基因是一个原癌基因，编码一种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发挥重要作用。为探讨HPC/ELAC2和HER2基因与日本PCa的相关性，我们分析了散发性PCa患者和正常对照HPC/ELAC2基因Ser257Leu和Ala541Thr、HER-2基因Ile655Val的多态位点频率。对照组为无血缘关系的日本男性，他们没有癌症病史，包括前列腺癌和正常的PSA水平(低于4.0 ng/m1)。结果：PCa组HPC/ELAC2基因Thr541频率(8.4%)显著高于对照组(2.1%)(p=0.0030，OR=4.02)。HER-2基因Va1655在PCa中的分布频率显著低于对照组(14.7%vs.26.2%，p=0.0025，OR=0.476)。结论：Her-2基因Thr541在日本散发性PCa的易感性中具有重要意义(OR=4.02)。Thr541基因多态在美国首次被报道与家族性前列腺癌有关。在我们的分析中，在日本的零星病例中也观察到了类似的现象。而在日本的PCa患者中，HER2中Va1655的频率明显较低。这个Va1655Val基因此前曾被报道在乳腺癌患者中的频率显著升高。前列腺癌和乳腺癌之间的这种相反的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.