title: ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers.
abstract: BACKGROUND
  Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers.
  
  
  METHODS
  We investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers [protein expression (n = 194 patients), mRNA expression (n = 156 patients)] and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours.
  
  
  RESULTS
  High ATM protein expression was associated with serous cystadenocarcinomas (p = 0.021) and platinum resistance (p = 0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p = 0.006) and advanced stage tumours (p = 0.018). High ATM protein (p = 0.001), high ATM mRNA (p = 0.018), high DNA-PKcs protein (p = 0.002), high DNA-PKcs mRNA (p = 0.044) and high ATR protein (p = 0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p = 0.006) and high ATR (p = 0.043) protein expressions remain independently associated with poor OCSS.
  
  
  CONCLUSIONS
  ATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer.
  
  
  CONCLUSIONS
  The data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Coveney
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK ; Laboratory of Molecular Oncology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Perry
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Kerstie
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kent
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK ; Laboratory of Molecular Oncology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
keywords: ATM; ATR; Biomarker; DNA-PK; Ovarian cancer