title: Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer.
abstract: OBJECTIVE
  Our aim was to investigate whether and at what stage hypermethylation of the tachykinin-1 (TAC1) gene is associated with human esophageal neoplastic transformation.
  
  
  METHODS
  TAC1 promoter hypermethylation was examined by real-time methylation-specific PCR in 258 human esophageal specimens and 126 plasma samples from patients or tissues at various stages of neoplastic evolution.
  
  
  RESULTS
  TAC1 hypermethylation in tissue samples showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P < 0.0001). Both frequencies and normalized methylation values of TAC1 tissue methylation were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's esophagus, EAC, and ESCC than in normal esophagus (P < 0.01). The frequency of TAC1 hypermethylation increased dramatically and early during neoplastic progression, from 7.5% in normal esophagus to 55.6% in BE from patients with Barrett's metaplasia alone, 57.5% in dysplastic Barrett's esophagus, and 61.2% in EAC. There was a significant relationship between TAC1 hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Twelve (50%) of 24 ESCC exhibited TAC1 hypermethylation. Overall patient survival correlated significantly with TAC1 methylation status in ESCC patients (mean survival, 22 versus 110 months; P = 0.0102, log-rank test), but not in EAC patients. Both mean normalized methylation values and frequency of TAC1 hypermethylation in plasma samples were significantly higher in EAC patients than in control subjects. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced TAC1 methylation and increased TAC1 mRNA expression.
  
  
  CONCLUSIONS
  TAC1 promoter hypermethylation is a common event in both major histologic types of human esophageal carcinoma, occurs early, correlates with other progression risk factors in esophageal adenocarcinogenesis, and is a tissue biomarker of a poor prognosis in ESCC. Circulating methylated TAC1 promoter DNA also offers potential as a biomarker for the diagnosis of EAC.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Alexandru
authors.initials: A
authors.lastname: Olaru
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Kan
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
authors.forename: Carmit
authors.initials: C
authors.lastname: Mantzur
authors.forename: Bogdan
authors.initials: B
authors.lastname: Paun
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Suna
authors.initials: S
authors.lastname: Wang
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: Rachana
authors.initials: R
authors.lastname: Agarwal
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012306:Risk; D012680:Sensitivity and Specificity; D015320:Tachykinins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D015320:Tachykinins; D012313:RNA; D004247:DNA