Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation

Ann Surg Oncol. 2013 Dec;20 Suppl 3:S583-9. doi: 10.1245/s10434-013-3043-1. Epub 2013 Jun 7.

Abstract

Background: Barrett esophagus develops in a scenario of chronic inflammation, linked to free radical formation and oxidative DNA damage. Eight-hydroxydeoxyguanosine, the main oxidative DNA adduct, is partially repaired by a glycosylase (OGG1) whose polymorphism is associated to a reduced repair capacity. Telomeres are particularly prone to oxidative damage, which leads to shortening and cell senescence, while elongation, by telomerase activity, is linked to cell immortalization and cancer. Limited data are available on this point with respect to Barrett esophagus. This study aimed to evaluate the link among 8-hydroxydeoxyguanosine, OGG1 polymorphism, telomerase activity, telomere length, and p53 mutation in Barrett progression.

Methods: Forty consecutive patients with short- and long-segment Barrett esophagus and 20 controls with gastroesophageal reflux disease without Barrett esophagus were recruited. Analysis of biopsy samples was undertaken to study 8-hydroxydeoxyguanosine levels, OGG1 polymorphism, telomerase activity, and telomere length. Serum samples were obtained for p53 mutation.

Results: Controls had significantly lower levels of 8-hydroxydeoxyguanosine and telomerase activity, with normal telomere length and no p53 mutation. In short-segment Barrett esophagus, 8-hydroxydeoxyguanosine levels were higher and telomeres underwent significant shortening, with stimulation of telomerase activity but no p53 mutations. In long-segment Barrett esophagus, 8-hydroxydeoxyguanosine reached maximal levels, with telomere elongation, and 42 % of the patients showed p53 mutation.

Conclusions: In Barrett patients, with disease progression, oxidative DNA damage accumulates, causing telomere instability, telomerase activation, and, in a late phase, mutations in the p53 gene, thus abrogating its activity as the checkpoint of proliferation and apoptosis, and facilitating progression to cancer.

Publication types

  • Comparative Study

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Adult
  • Aged
  • Aged, 80 and over
  • Autoantibodies / blood
  • Barrett Esophagus / genetics
  • Barrett Esophagus / metabolism
  • Barrett Esophagus / pathology*
  • Case-Control Studies
  • DNA Damage / genetics*
  • DNA Glycosylases / genetics
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Mucous Membrane / metabolism
  • Mucous Membrane / pathology*
  • Mutation / genetics*
  • Oxidation-Reduction
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Prognosis
  • Telomerase / metabolism
  • Telomere / genetics*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Autoantibodies
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • 8-Hydroxy-2'-Deoxyguanosine
  • TERT protein, human
  • Telomerase
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human
  • Deoxyguanosine