Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis.
BACKGROUND
The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis.


METHODS
SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC).


RESULTS
SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05).


CONCLUSIONS
SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus.
Jin
Zhe
Z
Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Mori
Yuriko
Y
Hamilton
James P
JP
Olaru
Alexandru
A
Sato
Fumiaki
F
Yang
Jian
J
Ito
Tetsuo
T
Kan
Takatsugu
T
Agarwal
Rachana
R
Meltzer
Stephen J
SJ
D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use; D001471:Barrett Esophagus / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D013004:Somatostatin / Q000235:genetics*
D013004:Somatostatin; D001374:Azacitidine