Promoter hypermethylation of p16INK4a, E-cadherin, O6-MGMT, DAPK and FHIT in adenocarcinomas of the esophagus, esophagogastric junction and proximal stomach.
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.
Schildhaus
Hans-Ulrich
HU
Department of Pathology, Otto von Guericke University, D-39120 Magdeburg, Germany.
Kröckel
Ivonne
I
Lippert
Hans
H
Malfertheiner
Peter
P
Roessner
Albert
A
Schneider-Stock
Regine
R
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D004938:Esophageal Neoplasms / Q000235:genetics*; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16; D064550:Death-Associated Protein Kinases; D009363:Neoplasm Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000099170:Bis(5'-adenosyl)triphosphatase