title: 53BP1 expression in sporadic and inherited ovarian carcinoma: Relationship to genetic status and clinical outcomes.
abstract: OBJECTIVE
  53BP1, a critical mediator of the DNA damage response, functions by regulating the balance between homologous recombination (HR) and the more error-prone non-homologous endjoining (NHEJ). Deletion of 53BP1 in brca1 (but not brca2) null cells partially restores HR and reverses sensitivity to poly-ADP-ribose polymerase inhibitors (PARPi). We characterized 53BP1 and BRCA1 expression and their association with clinical outcomes in sporadic and inherited ovarian carcinomas.
  
  
  METHODS
  We evaluated 53BP1 and BRCA1 protein expression using immunohistochemistry in 248 ovarian carcinomas and mRNA expression in 89 cases with quantitative reverse transcriptase PCR. All subjects were comprehensively characterized for germline mutations in BRCA1 and BRCA2.
  
  
  RESULTS
  BRCA1-mutated (but not BRCA2-mutated) ovarian carcinomas had significantly higher 53BP1 protein expression than wildtype carcinomas. 53BP1 message levels were significantly associated with BRCA1 message levels in wildtype and BRCA1-mutated but not BRCA2-mutated carcinomas. In wildtype carcinomas, lower 53BP1 message predicted improved survival (p=0.02, median survival 74 vs. 41months, HR 0.49, 95% CI 0.27-0.88). Survival was not impacted by BRCA1 message level. 53BP1 expression was not associated with primary platinum resistance. In 54 paired primary and recurrent cases, 53BP1 protein expression was equally likely to decrease or increase, and there was no association between decreased 53BP1 at recurrence and the development of platinum resistance.
  
  
  CONCLUSIONS
  BRCA1-mutated ovarian carcinomas have higher 53BP1 protein expression than wildtype or BRCA2-mutated carcinomas, in opposition to previous findings in breast carcinomas. Higher 53BP1 protein, which promotes NHEJ, could explain the frequent chromosomal aberrations that are characteristic of BRCA1-mutated ovarian carcinomas. In wildtype ovarian carcinomas, decreased 53BP1 message predicts improved survival, but message and protein expression were not associated.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Pennington
authors.forename: Anneka
authors.initials: A
authors.lastname: Wickramanayake
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Norquist
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pennil
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Garcia
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Agnew
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Piri
authors.initials: P
authors.lastname: Welcsh
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D005185:Fallopian Tube Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1