Roa Juan Carlos, Anabalón Leonardo, Roa Iván, Melo Angélica, Araya Juan Carlos, Tapia Oscar, de Aretxabala Xavier, Muñoz Sergio, Schneider Barbara
Department of Pathology, Faculty of Medicine, Universidad de La Frontera, Manuel Montt 112, Temuco, 478-1176, Chile.
J Gastroenterol. 2006 Mar;41(3):269-75. doi: 10.1007/s00535-005-1752-3.
Methylation in the promoter region of genes is an important mechanism of inactivation of tumor suppressor genes. Our objective was to analyze the methylation pattern of some of the genes involved in carcinogenesis of the gallbladder, examining the immunohistochemical expression of proteins, clinical features, and patient survival time.
Twenty cases of gallbladder cancer were selected from the frozen tumor bank. The DNA extracted was analyzed by means of a methylation-specific polymerase chain reaction test for the CDKN2A (p16), MLH1, APC, FHIT, and CDH1 (E-cadherin) genes. Morphological and clinical data and follow-up information were obtained.
All cases were in an advanced stage: histologically moderate or poorly differentiated tumors (95%). Methylation of the promoter area of genes was observed in 5%, 20%, 30%, 40%, and 65% of cases, and an altered immunohistochemical pattern (AIP) in 5%, 35%, 21%, 25%, and 66% for the MLH1, CDKN2A, FHIT, APC, and CDH1 genes, respectively. The Kappa concordance index between methylation of the promoter area and AIP for the MLH1 and CDH1 genes was very high (K > 0.75) and substantial for APC (K > 0.45). No correlation was found between survival time and the methylation of the genes studied.
The high frequency of gene methylation (with the exception of MLH1) and the high agreement between AIP and methylation of the gene promoter area for the MLH1, APC, and CDH1 genes suggest that the inactivation of tumor suppressor genes and of the genes related to the control of cellular proliferation through this mechanism is involved in gallbladder carcinogenesis.
基因启动子区域的甲基化是肿瘤抑制基因失活的重要机制。我们的目的是分析一些参与胆囊致癌过程的基因的甲基化模式，检测蛋白质的免疫组化表达、临床特征及患者生存时间。
从冷冻肿瘤库中选取20例胆囊癌病例。提取的DNA通过甲基化特异性聚合酶链反应检测CDKN2A（p16）、MLH1、APC、FHIT和CDH1（E-钙黏蛋白）基因。获取形态学和临床数据以及随访信息。
所有病例均处于晚期：组织学上为中度或低分化肿瘤（95%）。基因启动子区域甲基化在5%、20%、30%、40%和65%的病例中被观察到，MLH1、CDKN2A、FHIT、APC和CDH1基因免疫组化模式改变（AIP）分别为5%、35%、21%、25%和66%。MLH1和CDH1基因启动子区域甲基化与AIP之间的Kappa一致性指数非常高（K>0.75），APC基因的一致性指数较高（K>0.45）。未发现生存时间与所研究基因的甲基化之间存在相关性。
基因甲基化的高频率（MLH1除外）以及MLH1、APC和CDH1基因AIP与基因启动子区域甲基化之间的高度一致性表明，通过这种机制肿瘤抑制基因以及与细胞增殖控制相关基因的失活参与了胆囊致癌过程。
