Kim Ji Hun, Jung Eun Ji, Lee Hye Seung, Kim Min A, Kim Woo Ho
Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Oncol Rep. 2009 May;21(5):1251-9. doi: 10.3892/or_00000348.
Metastasis is a multi-step process involving many biomolecular changes and DNA methylation is one such molecular change. Although differences in DNA methylation have been reported in matched primary and metastatic mammary carcinoma, no such differences have been reported in gastric carcinoma. Accordingly, to investigate whether DNA methylation profiles in metastatic gastric carcinoma differ from those of their primary counterparts, we investigated the DNA methylation of eleven genes, ADAM23, CDH1, FHIT, FLNC, GSTP1, ITGA4, LOX, RUNX3, THBS1, TIMP3, and UCHL1 in 74 matched human primary gastric carcinomas, lymph node metastases, non-neoplastic gastric mucosal, and uninvolved lymph node tissues by utilizing methylation-specific PCR. Seven of these genes (ADAM23, FLNC, ITGA4, LOX, RUNX3, TIMP3, and UCHL1) showed cancer-specific methylation, and three (CDH1, FHIT, and THBS1) showed cancer-unrelated methylation. GSTP1 was rarely methylated in any tissue type. Of the seven genes that showed cancer-specific methylation, FLNC was more frequently methylated in metastatic gastric carcinomas than in their primary counterparts (p=0.004). In addition, the average number of methylated genes in metastatic tumors was greater than that in primary tumors (p=0.004). The high-methylation group (cases with three or more genes methylated in primary tumors) was found to contain more women (p=0.031) and diffuse type tumors by Lauren classification (p=0.022). DNA methylation profiles were not found to affect prognosis. We suggest that promoter methylation of FLNC may be involved in the lymph node metastasis of gastric carcinoma and that the DNA methylation statuses of metastatic tumors should be considered in node-positive gastric carcinoma.
转移是一个多步骤过程，涉及许多生物分子变化，DNA甲基化就是其中一种分子变化。虽然在配对的原发性和转移性乳腺癌中已报道了DNA甲基化差异，但在胃癌中尚未有此类差异的报道。因此，为了研究转移性胃癌的DNA甲基化谱是否与其原发性对应物不同，我们利用甲基化特异性PCR研究了74例配对的人类原发性胃癌、淋巴结转移灶、非肿瘤性胃黏膜和未受累淋巴结组织中11个基因（ADAM23、CDH1、FHIT、FLNC、GSTP1、ITGA4、LOX、RUNX3、THBS1、TIMP3和UCHL1）的DNA甲基化情况。其中7个基因（ADAM23、FLNC、ITGA4、LOX、RUNX3、TIMP3和UCHL1）显示出癌症特异性甲基化，3个基因（CDH1、FHIT和THBS1）显示出与癌症无关的甲基化。GSTP1在任何组织类型中很少发生甲基化。在显示癌症特异性甲基化的7个基因中，FLNC在转移性胃癌中比在其原发性对应物中更频繁地发生甲基化（p = 0.004）。此外，转移性肿瘤中甲基化基因的平均数量大于原发性肿瘤（p = 0.004）。高甲基化组（原发性肿瘤中有三个或更多基因甲基化的病例）中女性更多（p = 0.031），根据劳伦分类法为弥漫型肿瘤（p = 0.022）。未发现DNA甲基化谱影响预后。我们认为FLNC的启动子甲基化可能参与胃癌的淋巴结转移，并且在淋巴结阳性胃癌中应考虑转移性肿瘤的DNA甲基化状态。
