title: Expression of DNA damage response proteins in cervical cancer patients treated with radical chemoradiotherapy.
abstract: The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage.
  
  
  
  We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer. We compared expression to clinicopathologic correlates to determine prognostic significance.
  
  
  
  Five-year progression-free survival was significantly lower in the low expressors than in high expressors of ATM (35% vs. 58%, p=0.044) and PARP-1 (24% vs. 61%, p=0.003), and showed a trend to significance for DNA-PKcs (30% vs. 60%, p=0.050). Low expression of the same proteins also correlated significantly with lower overall survival. In multivariable analysis, adjusted for FIGO stage and tumor size, low ATM and PARP-1 expression was significantly associated with both poorer progression-free and overall survival. Pairwise analyses indicated that expression levels of these proteins were correlated.
  
  
  
  Expression of DNA damage response proteins in cervical cancer is associated with outcome in patients treated with CRT. Immunohistochemical analysis of these proteins may be useful in guiding treatment decisions in such patients.
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: C K
authors.initials: CK
authors.lastname: Ho
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: E N
authors.initials: EN
authors.lastname: Kornaga
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: A C
authors.initials: AC
authors.lastname: Klimowicz
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: E K
authors.initials: EK
authors.lastname: Enwere
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: G D
authors.initials: GD
authors.lastname: Bebb
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Phan
authors.affiliation: Department of Gynecologic Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Ghatage
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.
authors.forename: A M
authors.initials: AM
authors.lastname: Magliocco
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada; Department of Biochemistry and Molecular Biology, Health Science Building, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
authors.forename: S P
authors.initials: SP
authors.lastname: Lees-Miller
authors.affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, 1331 29th Street NW, Calgary, Alberta T2N 4N2, Canada. Electronic address: Corinne.Doll@albertahealthservices.ca.
authors.forename: C M
authors.initials: CM
authors.lastname: Doll
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000627:therapeutic use*; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005453:Fluorescence; D006801:Humans; D007150:Immunohistochemistry; D000072200:Ku Autoantigen / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D011379:Prognosis; D011878:Radiotherapy; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D000072200:Ku Autoantigen; D002945:Cisplatin
keywords: ATM; Cervical cancer; Chemoradiotherapy; DNA-PKcs; PARP-1