Jerónimo Carmen, Varzim Graça, Henrique Rui, Oliveira Jorge, Bento Maria José, Silva Cristina, Lopes Carlos, Sidransky David
Department of Pathology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal.
Cancer Epidemiol Biomarkers Prev. 2002 May;11(5):445-50.
The GSTP1 gene encodes for an enzyme, glutathione S-transferase pi (GSTpi),involved in detoxification of carcinogens. An aminoacid substitution (I105V) in GSTP1 produces a variant enzyme with lower activity and less capability of effective detoxification. This variant GSTP*B allele has been associated with a propensity to develop several neoplasms. Because GSTP1 promoter hypermethylation and inactivation of GSTpi expression is a frequent alteration in prostate carcinoma, we hypothesized that this somatic epigenetic modification could obviate any reduced enzyme activity caused by the germ-line polymorphism. We tested for the GSTP1 genotype in a population of prostate cancer patients, and in a control group composed of patients with benign prostatic hyperplasia (BPH) and healthy blood donors. Tissue samples from the 105 prostate cancer cases (105 adenocarcinomas and 34 prostatic intraepithelial neoplasia lesions), and from 43 BPH patients were tested for GSTP1 hypermethylation by methylation-specific PCR. GSTpi protein expression was assessed by immunohistochemistry. No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75). Moreover, no association was found between this genotype and tumor or BPH methylation status. Patients with unmethylated carcinomas did not disclose significant differences in genotypic distribution compared with the control population. In adenocarcinoma, a strong association (P < 0.00001) between GSTP1 promoter hypermethylation and loss of GSTpi expression was observed; however, this trend was not retained in prostatic intraepithelial neoplasia or BPH lesions. Although the GSTP1 polymorphism is not associated with altered susceptibility to prostate cancer, somatic promoter hypermethylation is an effective, but not the only, cause of decreased GSTpi function.
GSTP1基因编码一种酶，即谷胱甘肽S-转移酶π（GSTpi），它参与致癌物的解毒过程。GSTP1中的一个氨基酸替换（I105V）产生了一种活性较低且有效解毒能力较弱的变异酶。这种变异的GSTP*B等位基因与发生多种肿瘤的倾向有关。由于GSTP1启动子高甲基化以及GSTpi表达失活在前列腺癌中是一种常见的改变，我们推测这种体细胞表观遗传修饰可能消除由种系多态性引起的任何酶活性降低。我们在一组前列腺癌患者以及由良性前列腺增生（BPH）患者和健康献血者组成的对照组中检测了GSTP1基因型。通过甲基化特异性PCR检测了105例前列腺癌病例（105例腺癌和34例前列腺上皮内瘤变病变）以及43例BPH患者的组织样本中的GSTP1高甲基化情况。通过免疫组织化学评估GSTpi蛋白表达。与对照组相比，未检测到GSTP1基因型对前列腺癌风险有显著影响（优势比，1.02；95%置信区间，0.59 - 1.75）。此外，未发现该基因型与肿瘤或BPH甲基化状态之间存在关联。与对照组相比，未甲基化癌患者的基因型分布未显示出显著差异。在腺癌中，观察到GSTP1启动子高甲基化与GSTpi表达缺失之间存在强关联（P < 0.00001）；然而，这种趋势在前列腺上皮内瘤变或BPH病变中未保留。尽管GSTP1多态性与前列腺癌易感性改变无关，但体细胞启动子高甲基化是GSTpi功能降低的一个有效但并非唯一的原因。
