title: NcoI TNF-β gene polymorphism and TNF expression are associated with an increased risk of developing Barrett's esophagus and esophageal adenocarcinoma.
abstract: OBJECTIVE
  Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent anti-neoplastic agent, hence DNA polymorphisms that reduce TNF levels potentially enhance the development of BE and EAC. The aim of the study was to determine the impact of TNF gene variation on the RE-BE-EAC cascade.
  
  
  METHODS
  DNA from 887 Caucasian participants (197 controls, 305 RE, 257 BE, 128 EAC) was tested for the gene polymorphism TNF-β NcoI, and TNF production was determined by TNF-α specific immunohistochemistry on esophageal biopsies from these BE (n = 31) and EAC (n = 4) patients.
  
  
  RESULTS
  As compared with healthy controls, the TNF-β NcoI A/A genotype was significantly more prevalent in BE (p = 0.04) and EAC patients (p = 0.02), but not in RE patients (p = 0.1). While TNF-α protein levels were invariably high in esophageal biopsies from EAC patients, most esophageal BE samples showed low to moderate TNF levels.
  
  
  CONCLUSIONS
  Chronic inflammation, like in BE, markedly increase the risk of malignant transformation. In this study, the significantly higher frequency of the TNF-β NcoI A/A genotype and the local TNF expression indicate that the pro-inflammatory cytokine TNF plays a role in the development of BE and EAC.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Vivianda
authors.initials: V
authors.lastname: Menke
authors.forename: Katinka P M
authors.initials: KP
authors.lastname: van Zoest
authors.forename: Leon M G
authors.initials: LM
authors.lastname: Moons
authors.forename: Bettina
authors.initials: B
authors.lastname: Hansen
authors.forename: Raymond G J
authors.initials: RG
authors.lastname: Pot
authors.forename: Peter D
authors.initials: PD
authors.lastname: Siersema
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Kusters
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; C052380:endodeoxyribonuclease NcoI; D015252:Deoxyribonucleases, Type II Site-Specific