乳腺癌中BRCA1、GSTP1和MGMT基因甲基化检测的临床意义

Clinical significance of BRCA1,GSTP1 and MGMT gene methylation status in breast cancer

背景与目的:DNA甲基化是1种调节基因表达的重要机制,在肿瘤发生、发展中起重要作用。研究表明,在肿瘤诊断、预后及疗效判断方面,DNA甲基化是1种有潜在应用价值的肿瘤标志物。本研究通过对乳腺癌中组织标本中BRCA1,GSTP1和MGMT这3种与DNA修复功能有关基因的甲基化状态进行检测,探讨其临床应用价值。方法:在106例配对的乳腺癌及癌旁组织中,运用甲基化特异性PCR法,对BRCA1、GSTP1和MGMT基因的甲基化状况进行检测,统计分析它们与乳腺癌主要临床病理特征之间的关系。结果:在乳腺癌组织标本中,BRCA1、GSTP1和MGMT的甲基化频率分别为24.5%(26/106)、29.2%(31/106)和18.9%(20/106),明显高于对应癌旁组织7.5%(8/106)、11.3%(12/106)和4.7%(5/106)的甲基化频率,差异有统计学意义(P<0.01)。在肿瘤组织和癌旁组织中,至少有1种基因发生甲基化的分别为50.9%(54/106)和19.8%(21/106),每个标本的平均甲基化数分别为0.73和0.24,差异有统计学意义(P<0.000 1)。BRCA1基因甲基化与患者的年龄及ER(-)呈显著正相关(P=0.007和0.020);MGMT基因甲基化与乳腺癌分期、组织学分级和淋巴结转移呈显著正相关(P=0.016,0.025和0.030);GSTP1基因甲基化与淋巴结转移、肿瘤大小呈显著正相关(P=0.028和0.033);同时有超过1种基因甲基化与乳腺癌较晚的病理分期及淋巴转移正相关(P=0.028和0.007)。结论:BRCA1、GSTP1和MGMT基因甲基化状况与乳腺癌临床病理特征显著相关,同时存在多个基因甲基化预示着乳腺癌具有侵袭性表型,联合检测3者的甲基化状况可能对乳腺癌预后预测具有重要价值。

Background and purpose： DNA methylation is an important mechanism for regulating gene expression, and plays an important role in the tumorigenesis. Study shows that DNA methylation is a potentially promising biomarker in tumor diagnosis, prognosis as well as treatment selection. This study aimed to analyze the methylation status and assessed possible clinical value of 3 DNA repair genes BRCA1, GSTP1 and MGMT in breast cancer samples of Chinese women. Methods：Using methylation speciifc PCR （MSP）, we analyzed the methylation status of 3 DNA repair genes BRCA1, GSTP1 and MGMT in 106 paired breast tumors and corresponding normal tissues. Results： The methylation rates of BRCA1, GSTP1 and MGMT were 24.5% （26/106）, 29.2% （31/106） and 18.9%（20/106） in breast cancer tissues, which were higher than those （7.5%, 11.3%and 4.7%） in paired normal breast tissues, respectively （P〈0.01）. Methylation in at least one of the genes was found in 50.9%（54/106） of the breast cancer and 19.8%（21/106） in paired normal breast tissues. And the mean number of genes hypermethylated in each tumor and paired normal breast tissues were 0.73 and 0.24, respectively （P〈0.000 1）. The methylation status of BRCA1 was more frequent in the younger patients than in the older patients （P=0.007） and most BRCA1 methylated patients were ER negative （P=0.020）. Methylation status of GSTP1 was signiifcantly correlated with tumor size, lymph node metastasis （P=0.028 and 0.033, respectively）. MGMT methylation was significantly correlated with tumor stage, higher tumor grade and lymph node metastasis （P=0.016, 0.025 and 0.030, respectively）. High frequency simultaneous methylation of these 3 genes was more often in those with higher tumor stage and lymph node metastasis （P=0.028 and 0.007, respectively）. Conclusion：Hypermethylation of BRCA1, GSTP1 and MGMT genes may be linked to various known clinicopathological features of breast cancer in Chinese women, and the increasing multiple gene methylation in tumors may indicate an aggressive phenotype for breast cancer. Detection of the methylation status of these genes may be useful for identifying patients at high risk for breast cancer.