title: Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae.
abstract: DNA methylation changes are known to occur in gastric cancers and in premalignant lesions of the gastric mucosae. In order to examine variables associated with methylation levels, we quantitatively evaluated DNA methylation in tumors, non-tumor gastric mucosae, and in gastric biopsies at promoters of 5 genes with methylation alterations that discriminate gastric cancers from non-tumor epithelia (EN1, PCDH10, RSPO2, ZIC1, and ZNF610). Among Colombian subjects at high and low risk for gastric cancer, biopsies from subjects from the high-risk region had significantly higher levels of methylation at these 5 genes than samples from subjects in the low risk region (p ≤ 0.003). When results were stratified by Helicobacter pylori infection status, infection with a cagA positive, vacA s1m1 strain was significantly associated with highest methylation levels, compared with other strains (p = 0.024 to 0.001). More severe gastric inflammation and more advanced precancerous lesions were also associated with higher levels of DNA methylation (p ≤ 0.001). In a multivariate model, location of residence of the subject and the presence of cagA and vacA s1m1 in the H. pylori strain were independent variables associated with higher methylation in all 5 genes. High levels of mononuclear cell infiltration were significantly related to methylation in PCDH10, RSPO2, and ZIC1 genes. These results indicate that for these genes, levels of methylation in precancerous lesions are related to H. pylori virulence, geographic region and measures of chronic inflammation. These genes seem predisposed to sustain significant quantitative changes in DNA methylation at early stages of the gastric precancerous process.
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Schneider
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA; Holmes Regional Medical Center; Melbourne, FL USA.
authors.forename: Liviu A
authors.initials: LA
authors.lastname: Sicinschi
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Robertino
authors.initials: R
authors.lastname: Mera
authors.affiliation: Department of Surgery; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Dun-Fa
authors.initials: DF
authors.lastname: Peng
authors.affiliation: Department of Pathology; School of Medicine; Pontificia Universidad Catolica de Chile; Santiago, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Roa
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Thibaut
authors.initials: T
authors.lastname: de Sablet
authors.affiliation: Department of Pathology; School of Medicine; Universidad del Valle; Cali, Colombia.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Bravo
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA; Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research; Department of Veterans Affairs; Nashville, TN USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Surgery; Vanderbilt University Medical Center; Nashville, TN USA; Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research; Department of Veterans Affairs; Nashville, TN USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D000328:Adult; D019175:DNA Methylation; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology*; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D014774:Virulence
keywords: Helicobacter; Pyrosequencing; biopsy; chronic inflammation; gastric cancer; methylation