Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma

Abstract

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.