Genome-wide DNA methylation profiles altered by Helicobacter pylori in gastric mucosa and blood leukocyte DNA

// Yang Zhang 1, * , Xin-ran Zhang 1, * , Jong-lyul Park 2, * , Jong-hwan Kim 2 , Lian Zhang 1 , Jun-ling Ma 1 , Wei-dong Liu 3 , Da-jun Deng 4 , Wei-cheng You 1 , Yong-sung Kim 2 , Kai-feng Pan 1 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China 2 Medical Genomic Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea 3 Department of Medical Oncology, Healthy Bureau of Linqu County, Shandong, China 4 Department of Cancer Etiology, Peking University Cancer Hospital and Institute, Beijing, China * These authors contributed equally to this work Correspondence to: Kai-feng Pan, email: pankaifeng2002@yahoo.com Yong-sung Kim, email: yongsung@kribb.re.kr Keywords: H. pylori, gastric mucosa, blood leukocyte, methylation array Received: December 23, 2015      Accepted: April 24, 2016      Published: May 19, 2016 ABSTRACT Purpose: To investigate Helicobacter pylori (H.pylori) associated genome-wide aberrant methylation patterns in gastric mucosa and blood leukocyte DNA, a population-based study was conducted in Linqu County. Results: A total of 3000 and 386 CpGs were differentially methylated after successful H.pylori eradication in gastric mucosa and blood leukocyte DNA respectively, and 17 were the same alteration trend in the both tissues. The differentially methylated CpGs were located more frequently in promoters or CpG islands for gastric mucosa and gene body or open sea for blood leukocyte DNA. In eradicated gastric mucosa, the hypermethylated CpGs were enriched across inflammatory pathways, while the hypomethylated CpGs in tube morphogenesis, development and so on. The final validation found lower SPI1, PRIC285 and S1PR4 methylation levels in H.pylori positive subjects by case-control comparison, and increased methylation levels in H.pylori eradicated gastric mucosa by self-comparison. The Cancer Genome Atlas (TCGA) database analysis suggested that the up-regulation of the three genes by hypomethylation might be associated with gastric carcinogenesis. Experimental Design: Infinium HumanMethylation 450K BeadChip was used to compare methylation profiles prior to and after eradication treatment. The methylation levels of identified candidate differentially methylated genes before and after H.pylori eradication were further validated by two stages (Stage I: self-comparison of 16 subjects before and after anti- H.pylori treatment; Stage II: case-control comparison of 25 H.pylori positive and 25 negative subjects and self-comparison of 50 anti- H.pylori treated subjects). Conclusions: Novel H.pylori associated aberrant methylated genes were identified across the whole genome both in gastric mucosa and blood leukocyte DNA.