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

Objective 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. Methods 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. Results 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). Conclusions 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.