title: Polymerase Epsilon Exonuclease Domain Mutations in Ovarian Endometrioid Carcinoma.
abstract: OBJECTIVE
  Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail.
  
  
  METHODS
  In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas.
  
  
  RESULTS
  We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence; however, this finding was not statistically significant (P = 0.59).
  
  
  CONCLUSIONS
  The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.
authors.affiliation: *Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital; †University of British Columbia, Vancouver; ‡Department of Pathology and Laboratory Medicine, Calgary Laboratory Services; §University of Calgary, Calgary, Canada; ∥Department of Gynecology and Obstetrics, Tübingen University, Tübingen, Germany; ¶Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital; #University of Alberta; **Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada; ††Department of Public Health Sciences, Medical University of South Carolina; ‡‡Hollings Cancer Center, Charleston, SC; and §§Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, Canada.
authors.forename: Lien N
authors.initials: LN
authors.lastname: Hoang
authors.forename: Melissa K
authors.initials: MK
authors.lastname: McConechy
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.forename: Michael
authors.initials: M
authors.lastname: Anglesio
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Malden
authors.initials: M
authors.lastname: Maassen
authors.forename: Stefan
authors.initials: S
authors.lastname: Kommoss
authors.forename: Bo
authors.initials: B
authors.lastname: Meng
authors.forename: Lynne
authors.initials: L
authors.lastname: Postovit
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.forename: Annette
authors.initials: A
authors.lastname: Staebler
authors.forename: Sara
authors.initials: S
authors.lastname: Brucker
authors.forename: Bernhard
authors.initials: B
authors.lastname: Krämer
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D017434:Protein Structure, Tertiary; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human