Although the incidence of Barrett's
carcinomas (BC) and proximal gastric
adenocarcinomas (PGC) is increasing, little is known about different epigenetic changes in these etiopathogenetically distinct entities. Therefore, 29
adenocarcinomas [10 BC, 7 PGC and 12
tumors of the esophagogastric junction (JC)] and corresponding non-
tumor controls (NT) were examined using methylation-specific PCR. The most striking result was a significantly higher promoter methylation frequency of
O6-methylguanine methyl
transferase (MGMT) in BC compared with JC and PGC (0.7 vs. 0.08 vs. 0.29, respectively; p = 0.011; methylation exclusively in
tumors), confirmed immunohistochemically by a significant loss of MGMT
protein in BC (p = 0.006). Therefore, MGMT might become a prognosticator and key for
chemotherapy with
alkylating agents in BC. Frequencies of p16INK4a promoter methylation were 0.5 (BC), 0.42 (JC) and 0.29 (PGC; n.s.), but methylation was almost absent in NT controls. As immunonegative
tumors slightly outnumber methylation-positive cases, other mechanisms of gene inactivation must be discussed. Methylation of
E-cadherin was rarely observed (1/10 BC, 0/12 JC and 2/7 PGC). This is the first report on promoter methylation of
death-associated protein kinase (DAPK) and fragile
histidine triad gene (FHIT) in BC; both DAPK (BC 0.7, JC 0.92 and PGC 0.86) and FHIT (BC 0.88, JC 1.0 and PGC 1.0) were found to be highly methylated, suggesting that epigenetic silencing of these
tumor suppressors is a common event in
adenocarcinomas of the upper gastrointestinal tract, including BC. DAPK (0.54 on average) and FHIT methylation (0.77 on average) were also observed in NT samples. This might constitute an early epigenetic precursor lesion in the normally-appearing tissue surrounding the
tumor.