Localization of specialized intestinal metaplasia and the molecular alterations in Barrett esophagus in a Japanese population: an analysis of biopsy samples based on the “Seattle” biopsy protocol

Abstract

Summary It remains unclear why Barrett's esophagus (BE)-associated adenocarcinoma (EAC) frequently occurs in the 0-3 o'clock area of the BE. The aims of this study were to clarify the localization of specialized intestinal metaplasia (SIM) as a precancerous lesion and of molecular alterations among different locations using four-quadrant biopsies based on the “Seattle” protocol. We prospectively evaluated microsatellite instability, methylation status at the APC, CDKN2A, hMLH1, RUNX3 and MGMT genes, the immunoreactivity of the monoclonal antibody Das-1 for the colonic phenotype, and Ki-67 staining in 10 early EACs and 128 biopsy samples from 32 BE patients. Among the molecular changes, only APC gene hypermethylation was an independent predictive marker of EAC (OR=24.4, p=0.01). SIM was more frequently identified in the 0-3 o'clock quadrant than in the 6-9 o'clock quadrant (p=0.08). The Ki-67 index was higher in SIM than in the columnar-lined epithelium (CLE) without goblet cells (p<0.0001), and in both SIM and CLE with Das-1 reactivity than in those without (p=0.04 and p=0.06, respectively). Furthermore, the index was relatively higher in the 0-3 o'clock quadrant than in the 6-9 o'clock quadrant in cases with Das-1 reactivity. RUNX3 methylation was more frequently found in SIM than in CLE (p=0.04), while the incidence of the other biomarkers did not show a significant difference between the 0-3 o'clock and 6-9 o'clock areas, nor between SIM and CLE. SIM with Das-1 reactivity, but not molecular alterations, in the 0-3 o'clock quadrant may have higher proliferative activity compared to the other areas of the BE.

Clinical Significance of O-6-Methylguanine-DNA-Methyltransferase Promoter Methylation in Patients with Esophageal Carcinoma: A Systematic Meta-Analysis

“…The silencing of the MGMT gene through promoter methylation has been reported in various carcinomas, including esophageal cancer [46,47]. In the current meta-analysis, MGMT promoter was found to be methylated in esophageal cancer, with a range of 12.8% [30] to 100% [22]. MGMT promoter methylation frequency ranged from 0% [37] to 62% [21] in nonmalignant controls.…”

“…When tissues infected with esophageal carcinoma were compared to nonmalignant tissue samples, an obvious evidence of heterogeneity was observed in our study (I 2 = 66.1% and p < 0.001), we removed these 2 studies [22,38], and re-calculated the pooled OR of the remaining 14 studies (OR = 3.70; 95% CI 2.81-4.88). The re-calculated OR remained significant, and heterogeneity from the remaining 14 studies was lacking (I 2 = 34.0% and p = 0.103).…”

“…Based on the selection criteria for the eligible studies, eventually 17 articles were identified in this meta-analysis [21,22,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] these studies included a total of 1,368 patients with esophageal carcinoma and 1,489 nonmalignant controls. Sixteen studies evaluated the association between MGMT promoter methylation and esophageal carcinoma risk in cancer vs. nonmalignant controls [21,22,[28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Eight studies with 928 esophageal carcinoma patients analyzed the correlation between MGMT promoter methylation and the clinical features [21, 27-30, 32, 36, 37].…”

“…We conducted a sensitivity analysis to determine the change of a single study on the pooled OR and heterogeneity by deleting an individual study. When we removed these 2 studies (Fukui et al [22] and Schulmann et al [38]), the overall OR was 3.70 (95% CI 2.81-4.88), with a decreased heterogeneity (I 2 = 34.0% and p = 0.103). …”

“…A significant correlation was found between MGMT promoter methylation and esophageal cancer in cancer vs. nonmalignant controls by Fukui et al [22]. Hence, some contradictory results regarding the frequency of MGMT promoter methylation in esophageal cancer and nonmalignant controls were reported.…”