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, 5 (2), 149-53

Differential LINE-1 Hypomethylation of Gastric Low-Grade Dysplasia From High Grade Dysplasia and Intramucosal Cancer

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Differential LINE-1 Hypomethylation of Gastric Low-Grade Dysplasia From High Grade Dysplasia and Intramucosal Cancer

Jeong Rok Lee et al. Gut Liver.

Abstract

Background/aims: Gastric epithelial dysplasia is considered a precancerous lesion with a variable clinical course. There is disagreement, however, regarding histology-based diagnoses, which has led to confusion in choosing a therapeutic plan. New objective markers are needed to determine which lesions progress to true malignancy. We measured LINE-1 methylation levels, which have been reported to strongly correlate with the global methylation level in gastric epithelial dysplasia and intramucosal cancer.

Methods: A total of 145 tissue samples were analyzed by two histopathologists. All tissues were excised by therapeutic endoscopic mucosal resection and paired with adjacent normal tissue samples. A modified long interspersed nucleotide elements-combined bisulfite restriction analysis (COBRA-LINE-1) method was used.

Results: Gastric epithelial dysplasia and intramucosal cancer tissues had significantly lower levels of LINE-1 methylation than adjacent normal gastric tissues. High-grade dysplasia and intramucosal cancer were distinguishable from low-grade dysplasia based on LINE-1 methylation levels. Furthermore, the distinction could be determined with high sensitivity and specificity, as shown by the receiver operating characteristic (ROC) curve (AUC, 0.82; 95% confidence interval, 0.74 to 0.88).

Conclusions: LINE-1 methylation levels may provide a diagnostic tool for identifying high-grade dysplasia and intramucosal cancer.

Keywords: Gastric epithelial dysplasia; Intramucosal cancer; LINE-1 methylation.

Figures

Fig. 1
Fig. 1
Assessment of LINE-1 hypomethylation status using the COBRA-LINE-1 method. Calculations are based on the ratio of the digested bands divided by the sum of the digested and undigested bands, as described in the materials and methods section.
Fig. 2
Fig. 2
LINE-1 hypomethylation levels in gastric epithelial dysplasia and intramucosal cancer. When compared to adjacent normal mucosa, gastric epithelial dysplasia and cancer tissues have significantly lower LINE-1 methylation levels. Box plots illustrate median values, 25th and 75th percentiles, and outliers on a linear scale. The unpaired t-test is applied for nonparametric statistical analysis, and a p value of less than 0.05 is considered significant. N, normal; T, tumor.
Fig. 3
Fig. 3
LINE-1 hypomethylation levels in gastric epithelial neoplasias categorized using the revised Vienna classification. When tissue samples are divided into three groups according to the revised Vienna classification, high-grade dysplasia and intramucosal cancer (category 4) shows significantly lower LINE-1 methylation levels than low-grade dysplasia (category 3). Box plots illustrate median values, 25th and 75th percentiles, and outliers on a linear scale. An unpaired t-test and one way ANOVA are applied for nonparametric statistical analyses, and a p value of less than 0.05 is considered significant.
Fig. 4
Fig. 4
Receiver operating characteristic (ROC) curve for the diagnosis of high-grade dysplasia/intramucosal cancer. Gastric high-grade dysplasia and intramucosal cancer are accurately diagnosed using LINE-1 methylation levels (AUC, 0.82; 95% confidence interval, 0.74 to 0.88).

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