Supplementary Material for: Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

<b><i>Background/Aims:</i></b> Human mutL homolog 1 (<i>MLH1</i>) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of <i>MLH1</i> promoter methylation in GC. <b><i>Methods:</i></b> The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. <b><i>Results:</i></b> A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. <i>MLH1</i> promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. <i>MLH1</i> promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, <i>H. pylori</i> infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. <i>MLH1</i> promoter methylation exhibited a poor sensitivity value (< 0.5) in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of <i>MLH1</i> promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. <b><i>Conclusions:</i></b> Our results suggest that the detection of <i>MLH1</i> promoter methylation may be a potential prognostic biomarker for GC patients with MSI.