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BackgroundGastric cancer (GC) is the fifth most prevalent cancer, and intestinal metaplasia (IM) is generally considered a precancerous lesion in the gastric carcinogenesis cascade. DNA methylation is one of the most deeply studied epigenetic modifications. Numerous studies have been shown that aberrant methylation of DOK7, an adaptor protein, and SPDEF, a transcription factor, correlates with carcinogenesis. This study aimed to investigate DNA methylation of DOK7 and SPDEF in the whole blood specimens obtained from patients with IM and GC and normal individual controls to examine the possible implication of epigenetic biomarker for differential diagnosis GC from IM.Material and MethodsBioinformatic analysis, differentially methylated regions (DMR) enrichment analysis, was conducted to detect appropriate epigenetic regions in DOK7 and SPDEF CpGs Island. The methylation of selected CPG regions of DOK7 and SPDEF was assayed on 95 blood samples, including 30 IM patients, 30 GC patients, and 35 normal controls individuals. After DNA extraction, MSRE-PCR was utilized to evaluate the loci methylation level, followed by real-time MSRE-PCR to quantify the region's methylation status.ResultsOur analysis indicated that DOK7 and SPDEF have significant hypermethylation in GC and IM versus the normal specimens. Significant methylation changes were observed for Dok7 between IM (p = 0.03), GC (p < 0.001) cases compared to normal controls. For SPDEF significant hypermethylation results obtained, for GC (p < 0.001) and IM (p = 0.03) cases in comparison to normal controls. Sensitivity and specificity for DOK7 as DNA epigenetic biomarker diagnostic of gastric cancer test were determined by ROC statistical analysis revealed high intermediate sensitivity (73.33 %) and high specificity (97.14 %) methylation changes with p < 0.001. For SPDEF DNA methylation test as GC biomarker by ROC statistical analysis revealed lower sensitivity (36.67 %) but higher specificity (97.14 %) with p < 0.001.ConclusionsThese results suggest that the change in the methylation of DOK7 (AUC = 0.9495) and SPDEF (AUC = 0.8419) is a promising epi-biomarker. For the first time, this study shows blood-based biomarkers DOK7 and SPDEF genes are powerful epi-biomarkers and provide insights into gastric cancer pathogenesis and diagnosis.