Promoter methylation of RNF180 is associated with H.pylori infection and serves as a marker for gastric cancer and atrophic gastritis
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Fang Han1,*, Li-ping Sun1,*, Shuang Liu1, Qian Xu1, Qiao-yi Liang2, Zhe Zhang3, Hai-chao Cao3, Jun Yu2, Dai-ming Fan3, Yong-zhan Nie3, Kai-chun Wu3, Yuan Yuan1
1Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China
2Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
3State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China
*These authors have contributed equally to this work
Yuan Yuan, e-mail: firstname.lastname@example.org
Kai-chun Wu, e-mail: email@example.com
Keywords: gastric cancer, atrophic gastritis, bisulfite genomic sequencing, CpG islands, methylation
Received: October 17, 2015 Accepted: March 06, 2016 Published: April 01, 2016
Promoter methylation (PM) of RING-finger protein (RNF) 180 affects gastric cancer (GC) prognosis, but its association with risk of GC or atrophic gastritis (AG) is unclear. We investigated relationships between RNF180 PM and GC or AG, and the effects of Helicobactor pylori (H.pylori) infection on RNF180 PM. This study included 513 subjects (159 with GC, 186 with AG, and 168 healthy controls [CON]) for RNF180 PM analysis, and another 55 GC patients for RNF180 gene expression analysis. Methylation was quantified using average methylation rates (AMR), methylated CpG site counts (MSC) and hypermethylated CpG site counts (HSC). RNF180 promoter AMR and MSC increased with disease severity. Optimal cut-offs were GC + AG: AMR > 0.153, MSC > 4 or HSC > 1; GC: AMR > 0.316, MSC > 15 and HSC > 6. Hypermethylation at 5 CpG sites differed significantly between GC/AG and CON groups, and was more common in GC patients than AG and CON groups for 2 other CpG sites. The expression of RNF180 mRNA levels in tumor were significantly lower than those in non-tumor, with the same as in hypermethylation than hypomethylation group. H.pylori infection increased methylation in normal tissue or mild gastritis, and increased hypermethylation risk at 3 CpG sites in AG. In conclusion, higher AMR, MSC and HSC levels could identify AG + GC or GC. Some RNF180 promoter CpG sites could identify precancerous or early-stage GC. H.pylori affects RNF180 PM in normal tissue or mild gastritis, and increases hypermethylation in 3 CpG sites in AG.
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