title: Diagnostic correlation between the expression of the DNA repair enzyme N-methylpurine DNA glycosylase and esophageal adenocarcinoma onset: a retrospective pilot study.
abstract: EAC in its early stages, when it can potentially be cured, is rarely symptomatic and is associated with high mortality rates because in part of late-stage diagnosis. Given that DNA repair is an important contributory factor of early-stage malignancy, our study focused on the expression of the base excision repair enzyme N-methylpurine DNA glycosylase (MPG) in EAC disease onset. MPG messenger RNA (mRNA) expression levels were determined using quantitative reverse transcriptase polymerase chain reaction from a maximum of 72 patient samples. Immunohistochemistry was further utilized for the detection of MPG protein, and semiquantitative analysis performed using an H-score approach was carried out on a total of 130 archival tissue samples of different esophageal pathologies. Nuclear localized MPG protein was detected in all nonmalignant tissues derived from the enterohepatic system, with H-score values of 3.9-5.5 ± 0.4-1.0. In cancerous tissues derived from the enterohepatic system, a 9.5-fold increase in the level of MPG mRNA expression was specifically observed in the malignant regions located within the esophagus region. Further analysis revealed a 9- and 14-fold increase in MPG mRNA expression in EAC tumor, node, metastasis stages II and III, respectively, suggesting MPG expression to correlate with EAC disease progression. Immunohistochemistry analysis further showed a sevenfold significant increase in MPG protein expression in EAC tissues. Intriguingly, there was a fivefold significant decrease in nuclear localized MPG protein expression in tissues derived from Barrett's esophagus and low-grade dysplasia. Such findings highlight a complex regulatory pattern governing DNA glycosylase base excision repair initiation, as normal tissue undergoes Barrett's metaplasia and later dedifferentiates to EAC. Indeed, disease-stage-specific alterations in the expression of MPG may highlight a potential role for MPG in determining EAC onset and thus potentially be of clinical relevance for early disease detection and increased patient survival.
authors.affiliation: Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK. z.zair@warwick.ac.uk
authors.forename: Z M
authors.initials: ZM
authors.lastname: Zaïr
authors.forename: G E
authors.initials: GE
authors.lastname: Johnson
authors.forename: A P
authors.initials: AP
authors.lastname: Griffiths
authors.forename: G J
authors.initials: GJ
authors.lastname: Jenkins
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000473:pathology / Q000556:secondary; D001471:Barrett Esophagus / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D045647:DNA Glycosylases / Q000032:analysis* / Q000235:genetics; D004260:DNA Repair; D018450:Disease Progression; D055088:Early Detection of Cancer; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D007684:Kidney Tubules / Q000166:cytology; D008198:Lymph Nodes / Q000473:pathology; D050527:Mesangial Cells / Q000648:ultrastructure; D008679:Metaplasia; D009367:Neoplasm Staging; D010295:Parietal Cells, Gastric / Q000648:ultrastructure; D010865:Pilot Projects; D011230:Precancerous Conditions / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D045647:DNA Glycosylases; C076131:DNA-3-methyladenine glycosidase II
keywords: Barrett's metaplasia; MPG; base excision repair; bile salts; esophageal adenocarcinoma