title: Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair.
abstract: OBJECTIVE
  Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues.
  
  
  METHODS
  We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC.
  
  
  RESULTS
  We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression ofEME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes includingXPC,XPA,DDB2,XPF, andXPG.
  
  
  CONCLUSIONS
  Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration ofEME1upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Robin I
authors.initials: RI
authors.lastname: Dewalt
authors.affiliation: Cardiothoracic Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kesler
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Zane T
authors.initials: ZT
authors.lastname: Hammoud
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: LeeAnn
authors.initials: L
authors.lastname: Baldridge
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Eyas M
authors.initials: EM
authors.lastname: Hattab
authors.affiliation: Division of Hematology/Oncology, Department of Medicine; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Shadia I
authors.initials: SI
authors.lastname: Jalal
keywords: DNA repair; MUS81/EME1; esophageal adenocarcinoma