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Research Article: Association of NDRG4 gene methylation in peripheral blood leukocytes with gastric cancer risk, chemotherapy efficacy and prognosis

Date Published: 2026-04-27

Abstract:
To analyze the functions of NDRG family genes in gastric cancer (GC) utilizing bioinformatics. Furthermore, the association between the methylation of NDRG4 gene in peripheral blood leukocytes (PBLs) and GC risk, chemotherapy efficacy, and prognosis was analyzed. Using TCGA and GEO databases, the study analyzed the expression, immune related signatures, methylation patterns and prognostic of NDRG family genes. Two-phase case-control study (310 GC patients and 300 controls) was conducted to investigate the association between the methylation of NDRG4 gene and GC risk. In addition, this study explored the association between methylation of NDRG4 gene and the therapeutic effect and prognosis of GC. The expression level of NDRG4 gene was compared between the hypermethylation and hypomethylation groups. The single nucleotide polymorphism (SNP) rs7202037 genotypes of 280 GC patients were detected, and the methylation level differences among rs7202037 genotypes were compared. Bioinformatics analysis showed that the expression of NDRG family genes was related to immunity and methylation ( P < 0.05). Two-phase case-control study found that the methylation of NDRG4-chr16:58497239 ( OR = 2.536, 95% CI = 1.514-4.248, P BH =0.004) and NDRG4-chr16:58497262 ( OR = 1.910, 95% CI = 1.223-2.981, P BH =0.020) sites were correlated with GC risk. The two CpG sites was also associated with chemotherapy efficacy ( P BH <0.05). The methylation of NDRG4-chr16:58497239 was correlated with progression free survival (PFS) of GC patients ( P BH =0.016). Compared with the hypermethylation group, NDRG4 was expressed higher in hypomethylation group ( P = 0.019). Methylation levels differed among different rs7202037 genotypes ( P < 0.05). The methylation of NDRG4 gene in PBLs was associated with GC risk, chemotherapy efficacy and prognosis. The rs7202037 variation could affect the methylation levels of NDRG4 gene. These findings provided new directions for exploring the pathogenesis of GC and screening non-invasive marker.

Introduction:
Gastric cancer (GC) is the second leading cause of cancer deaths worldwide ( 1 ). Globally, there were nearly one million new cases each year, resulting in over 650,000 deaths ( 2 ). Early detection is of great significance for reducing the disease burden and mortality rate of GC. However, many patients have already reached the advanced stage when they are diagnosed ( 3 ). Endoscopy is helpful for the early diagnosis of GC, but it is invasive and expensive ( 4 ). At present, blood-based biomarkers have great…

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