title: GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer.
abstract: BACKGROUND
  A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival.
  
  
  METHODS
  Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material.
  
  
  RESULTS
  Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression.
  
  
  CONCLUSIONS
  The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance.
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway. lars.eftang@medisin.uio.no.|Department of Gastrointestinal Surgery, Akershus University Hospital, N-1478, Nordbyhagen, Lørenskog, Norway. lars.eftang@medisin.uio.no.
authors.forename: Lars Lohne
authors.identifier: http://orcid.org/0000-0001-8416-4640
authors.initials: LL
authors.lastname: Eftang
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway.
authors.forename: Jovana
authors.initials: J
authors.lastname: Klajic
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.|Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.
authors.forename: Qin Ying
authors.initials: QY
authors.lastname: Esbensen
authors.affiliation: Department of Pathology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Gustav Peter
authors.initials: GP
authors.lastname: Blom
authors.affiliation: Institute of Clinical Medicine, Akershus University Hospital and University of Oslo, Lørenskog, Norway.
authors.forename: Ida Rashida Khan
authors.initials: IR
authors.lastname: Bukholm
authors.affiliation: Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.|Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Bukholm
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery*
chemical_list: D014408:Biomarkers, Tumor; C494993:GFRA3 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors
keywords: DNA methylation; GFRA3; Gastric cancer; Gene expression; Prognosis; Survival