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

Abstract

Purpose: Our aim was to investigate whether and at what stage hypermethylation of the tachykinin-1 (TAC1) gene is associated with human esophageal neoplastic transformation. Experimental Design: 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 ofTAC1 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.The tachykinin-1 (TAC1) gene has been mapped to chromosome 7q21-22 (1), a locus that frequently undergoes loss of heterozygosity in human cancers, including esophageal adenocarcinoma (EAC; refs. 2, 3). However, loss of heterozygosity is only one mechanism of gene inactivation; other common mechanisms include point mutation, homozygous deletion, and promoter methylation (4). It is now well established that promoter methylation correlates with transcriptional silencing in cancers (5), including esophageal squamous cell cancer (ESCC) and EAC (6, 7). Recently, data from our laboratory showed that the TAC1 promoter was methylated in 16 (47%) of 34 human colon cancers, and that the demethylating agent 5-aza-2 ¶-deoxycytidine (5-Aza-dC) reversed TAC1 promoter hypermethylation and restored TAC1 mRNA expression in colon cancer cell lines (8).

Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors

“…17,19,20,30,35 CDKN2A, ESR1 and MYOD1 were methylated only in BE from patients who possessed dysplasia or cancer in other regions of their esophagus, but not in patients with no evidence of progression beyond BE, while CALCA, MGMT and TIMP3 were methylated more frequently in normal stomach, normal esophageal mucosa and intestinal metaplasia from patients with distant dysplasia or esophageal cancer than from patients without dysplasia or cancer. 35 Previously, we demonstrated that hypermethylation of p16, RUNX3 and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC.…”

“…Promoter hypermethylation of CDH13 was analyzed in 66 NE, 60 BE (including 36 Ba and 24 Bt), 40 D (including 19 LGD and 21 HGD), 67 EAC, and 26 ESCC. CDH13 promoter hypermethylation showed highly discriminative ROC curve profiles and AUROCs, clearly distinguishing both EAC and ESCC from NE (Figs.…”

“…[16][17][18] Furthermore, there is a growing body of evidence showing that abnormal methylation of DNA can be an early event in carcinogenesis and can serve as an early cancer detection biomarker, 15 including in EAC. [17][18][19][20] Hypermethylation of CDH13 has been described in many human cancers, 8,14,[21][22][23][24][25][26][27][28][29] including ESCC 24,29 ; however, hypermethylation of CDH13 in precancerous lesions such as Barrett's metaplasia (BE), as well as in BE-associated EAC, is an area that still remains to be explored. We investigated hypermethylation of the CDH13 promoter by real-time quantitative methylation-specific PCR (qMSP) in 259 endoscopic esophageal biopsy specimens of differing histologies and correlated these data with clinicopathological features.…”

PIK3CA Mutation Is Associated with a Favorable Prognosis among Patients with Curatively Resected Esophageal Squamous Cell Carcinoma

“…Examining biomarkers or prognostic factors is important in cancer research (27)(28)(29)(30)(31). Previous studies examining the relationship between PIK3CA mutations and prognosis in human cancers have yielded variable results (Table 1; between PIK3CA mutations and a better prognosis has been shown in several small-sized studies (all n < 200) of breast cancer and ovarian cancer (32)(33)(34)(35).…”

Circulating DNA as a Biomarker for Early Detection of Cancer: A Brief Update with an Emphasis on Lung Cancer~!2010-06-09~!2010-08-03~!2010-09-06~!

“…Such studies have indicated a good correlation between restricted expression at the tissue level and the occurrence of detectable levels of candidate biomarkers in serum/plasma DNA. In this connection, the circulating methylated DNA approach has been applied as a biomarker in various forms of cancer, including pancreatic [19,20,24,25], ovarian [26][27][28][29], prostate carcinoma [30][31][32][33][34], hepatocellular carcinoma [35][36][37][38], esophageal adenocarcinoma [39,40], colorectal carcinoma [8,41,42], breast [3,[43][44][45], head and neck squamous cell carcinoma [46][47][48], non-Hodgkin lymphoma [49], and lung cancer [10,16,18,[50][51][52].…”