Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer.
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.
Jin
Zhe
Z
Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Olaru
Alexandru
A
Yang
Jian
J
Sato
Fumiaki
F
Cheng
Yulan
Y
Kan
Takatsugu
T
Mori
Yuriko
Y
Mantzur
Carmit
C
Paun
Bogdan
B
Hamilton
James P
JP
Ito
Tetsuo
T
Wang
Suna
S
David
Stefan
S
Agarwal
Rachana
R
Beer
David G
DG
Abraham
John M
JM
Meltzer
Stephen J
SJ
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*
D015415:Biomarkers; D014408:Biomarkers, Tumor; D015320:Tachykinins; D012313:RNA; D004247:DNA