Data from Hypermethylation of Tachykinin-1 Is a Potential Biomarker in Human Esophageal Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Our aim was to investigate whether and at what stage hypermethylation of the <i>tachykinin-1</i> (<i>TAC1</i>) gene is associated with human esophageal neoplastic transformation.</p><p><b>Experimental Design:</b><i>TAC1</i> 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.</p><p><b>Results:</b><i>TAC1</i> 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 (<i>P</i> < 0.0001). Both frequencies and normalized methylation values of <i>TAC1</i> tissue methylation were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's esophagus, EAC, and ESCC than in normal esophagus (<i>P</i> < 0.01). The frequency of <i>TAC1</i> 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 <i>TAC1</i> hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Twelve (50%) of 24 ESCC exhibited <i>TAC1</i> hypermethylation. Overall patient survival correlated significantly with <i>TAC1</i> methylation status in ESCC patients (mean survival, 22 versus 110 months; <i>P</i> = 0.0102, log-rank test), but not in EAC patients. Both mean normalized methylation values and frequency of <i>TAC1</i> 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 <i>TAC1</i> methylation and increased <i>TAC1</i> mRNA expression.</p><p><b>Conclusions:</b><i>TAC1</i> 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 <i>TAC1</i> promoter DNA also offers potential as a biomarker for the diagnosis of EAC.</p></div>