J Cancer 2021; 12(24):7326-7333. doi:10.7150/jca.64613 This issue
1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, 100142, People's Republic of China.
2. Linqu Public Health Bureau, Linqu, Shandong, 262600, People's Republic of China.
#These authors contributed equally to this work.
Background and Aim: Methylation alterations may be involved in Helicobacter pylori-associated gastric carcinogenesis. This study aims to explore the potential H.pylori-associated methylation biomarkers in blood leukocyte and gastric mucosa.
Methods: Five candidate H.pylori-associated aberrant methylation genes were selected from the previous genome-wide profiling panels and validated in blood leukocyte and gastric mucosa in multi-stages (case-control validation between H.pylori positive and negative subjects and self-control validation before and after anti-H.pylori treatment).
Results: GNAS methylation level was decreased in blood leukocyte (62.07% v.s. 46.33%, p<0.001) and gastric mucosa (56.30% v.s. 32.42%, p<0.001) of H.pylori positive subjects compared to negative controls. While, MTERF1 methylation level was increased significantly in blood leukocyte (29.57% v.s. 56.02%, p<0.001) and gastric mucosa (31.10% v.s. 47.50%, p<0.001) of positive subjects compared to controls. After successful H.pylori eradication, the methylation levels were increased from 44.87% to 60.88% (p<0.001) for GNAS and decreased from 46.19% to 34.56% (p<0.001) for MTERF1 in blood leukocyte. Similar increasing and decreasing methylation alterations were also found for the two genes after successful eradication in paired gastric mucosa. In TCGA database, an inverse relationship was found between GNAS methylation and mRNA expression (r=-0.12, p=0.027). The GC cases with higher GNAS expression levels showed significantly worse survival (HR, 2.09, 95%CI, 1.22-3.57, p=0.007) compared to lower expression subjects.
Conclusions: GNAS and MTERF1 methylation levels may be affected by H.pylori infection in gastric mucosa and blood leukocyte. GNAS may be involved in advanced stage of GC development, although the possible mechanism still needs further study in precancerous lesions.
Keywords: Gastric cancer, Helicobacter pylori, Methylation biomarker, Blood leukocyte, Gastric mucosa