title: Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors.
abstract: Although the CDH13 gene has been shown to undergo epigenetic silencing by promoter methylation in many types of tumors, hypermethylation of this gene in Barrett's-associated esophageal adenocarcinogenesis has not been studied. Two hundred fifty-nine human esophageal tissues were therefore examined for CDH13 promoter hypermethylation by real-time methylation-specific PCR. CDH13 hypermethylation showed discriminative receiver-operator characteristic curve profiles, sharply demarcating esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma (ESCC) and normal esophagus (NE) (p < 0.0001). CDH13 normalized methylation values (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE (D) and EAC than in NE (p < 0.0000001). CDH13 hypermethylation frequency was 0% in NE but increased early during neoplastic progression, rising to 70% in BE, 77.5% in D and 76.1% in EAC. Both CDH13 hypermethylation frequency and its mean NMV were significantly higher in BE with than without accompanying EAC. In contrast, only 5 (19.2%) of 26 ESCCs exhibited CDH13 hypermethylation. Furthermore, both CDH13 hypermethylation frequency and its mean NMV were significantly higher in EAC than in ESCC, as well as in BE or D vs. ESCC. Interestingly, mean CDH13 NMV was significantly lower in short-segment than in long-segment BE, a known clinical risk factor for neoplastic progression. Similarly, BE segment length was significantly lower in specimens with unmethylated than with methylated CDH13 promoters. 5-aza-2'-deoxycytidine treatment of OE33 EAC and KYSE220 ESCC cells reduced CDH13 methylation and increased CDH13 mRNA expression. These findings suggest that hypermethylation of CDH13 is a common, tissue-specific event in human EAC, occurs early during BE-associated neoplastic progression, and correlates with known clinical neoplastic progression risk factors.
authors: Division of Gastroenterology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors: Zhe
authors: Z
authors: Jin
authors: Yulan
authors: Y
authors: Cheng
authors: Alexandru
authors: A
authors: Olaru
authors: Takatsugu
authors: T
authors: Kan
authors: Jian
authors: J
authors: Yang
authors: Bogdan
authors: B
authors: Paun
authors: Tetsuo
authors: T
authors: Ito
authors: James P
authors: JP
authors: Hamilton
authors: Stefan
authors: S
authors: David
authors: Rachana
authors: R
authors: Agarwal
authors: Florin M
authors: FM
authors: Selaru
authors: Fumiaki
authors: F
authors: Sato
authors: John M
authors: JM
authors: Abraham
authors: David G
authors: DG
authors: Beer
authors: Yuriko
authors: Y
authors: Mori
authors: Yutaka
authors: Y
authors: Shimada
authors: Stephen J
authors: SJ
authors: Meltzer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D015820:Cadherins; D017931:DNA Primers; C099972:H-cadherin; D001374:Azacitidine