Abstract
Gene promoter methylation has been reported in gastric cancer (GC). However, the potential applications of blood-based gene promoter methylation as a noninvasive biomarker for GC detection remain to be evaluated. Hence, we performed this analysis to determine whether promoter methylation of 11 tumor-related genes could become a promising biomarker in blood samples in GC. We found that the cyclin-dependent kinase inhibitor 2A (p16), E-cadherin (CDH1), runt-related transcription factor 3 (RUNX3), human mutL homolog 1 (MLH1), RAS association domain family protein 1A (RASSF1A), cyclin-dependent kinase inhibitor 2B (p15), adenomatous polyposis coli (APC), Glutathione S-transferase P1 (GSTP1), TP53 dependent G2 arrest mediator candidate (Reprimo), and O6-methylguanine-DNAmethyl-transferase (MGMT) promoter methylation was notably higher in blood samples of patients with GC compared with non-tumor controls. While death-associated protein kinase (DAPK) promoter methylation was not correlated with GC. Further analyses demonstrated that RUNX3, RASSF1A and Reprimo promoter methylation had a good diagnostic capacity in blood samples of GC versus non-tumor controls (RUNX3: sensitivity = 63.2% and specificity = 97.5%, RASSF1A: sensitivity = 61.5% and specificity = 96.3%, Reprimo: sensitivity = 82.0% and specificity = 89.0%). Our findings indicate that promoter methylation of the RUNX3, RASSF1A and Reprimo genes could be powerful and potential noninvasive biomarkers for the detection and diagnosis of GC in blood samples in clinical practices, especially Reprimo gene. Further well-designed (multi-center) and prospective clinical studies with large populations are needed to confirm these findings in the future.
Highlights
Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of death in all human cancers worldwide [1]
We found that the cyclindependent kinase inhibitor 2A (p16), E-cadherin (CDH1), runt-related transcription factor 3 (RUNX3), human mutL homolog 1 (MLH1), RAS association domain family protein 1A (RASSF1A), cyclin-dependent kinase inhibitor 2B (p15), adenomatous polyposis coli (APC), Glutathione S-transferase P1 (GSTP1), TP53 dependent G2 arrest mediator candidate (Reprimo), and O6-methylguanine-DNAmethyl-transferase (MGMT) promoter methylation was notably higher in blood samples of patients with gastric cancer (GC) compared with non-tumor controls
No significant correlation was found between death-associated protein kinase (DAPK) promoter methylation and GC (OR = 7.82, 95% confidence intervals (95% CIs) = 0.92-66.26) (Figure 5)
Summary
Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of death in all human cancers worldwide [1]. Aberrant DNA methylation of tumor-related genes could be a noninvasive biomarker using body fluid samples (blood or urine etc.) for detecting cancer [8,9,10,11]. Human mutL homolog 1 (MLH1) encoding a DNA mismatch repair (MMR) protein and lack of MLH1 expression is associated with genomic instability in gastric cancer [16, 17]. RAS association domain family protein 1A (RASSF1A) as a TSG has some biological roles in the regulation of cell cycle, microtubule stability, and apoptosis [18]. Death-associated protein kinase (DAPK), a calcium/calmodulin-dependent serine/threonine kinase, is related to these functions of apoptosis, autophagy, and inflammation [23]. Multiple tumor-related genes are found to be commonly methylated in tissue samples in GC, such as p16, CDH1, RUNX3, MLH1, RASSF1A, p15, APC, DAPK, GSTP1, Reprimo, and MGMT etc. Multiple tumor-related genes are found to be commonly methylated in tissue samples in GC, such as p16, CDH1, RUNX3, MLH1, RASSF1A, p15, APC, DAPK, GSTP1, Reprimo, and MGMT etc. [22, 26,27,28]
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