title: Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer.
abstract: OBJECTIVE
  Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer.
  
  
  METHODS
  Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9).
  
  
  RESULTS
  A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD).
  
  
  CONCLUSIONS
  The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerecke
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Scholtka
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Löwenstein
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fait
authors.affiliation: Department of Internal Medicine, Gastroenterology and Interventional Endoscopy, Vivantes-Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Gottschalk
authors.affiliation: Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Rogoll
authors.affiliation: Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Melcher
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. kleuser@uni-potsdam.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D003092:Colitis / Q000150:complications* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D039001:Integrin alpha Chains / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000209:etiology / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014746:Vimentin / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D006023:Glycoproteins; D039001:Integrin alpha Chains; D014746:Vimentin; C021240:tissue-factor-pathway inhibitor 2
keywords: Biomarker; Colitis; Colon cancer; DNA methylation; Epigenetic; Gastrointestinal tract