title: BRCAness profile of sporadic ovarian cancer predicts disease recurrence.
abstract: BACKGROUND
  The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes.
  
  
  OBJECTIVE
  To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival.
  
  
  METHODS
  Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function.
  
  
  RESULTS
  High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03).
  
  
  CONCLUSIONS
  Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance.
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Weiya Z
authors.initials: WZ
authors.lastname: Wysham
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Laura
authors.initials: L
authors.lastname: Hays
authors.forename: Suzanna
authors.initials: S
authors.lastname: Syriac
authors.forename: Tijana
authors.initials: T
authors.lastname: Skrepnik
authors.forename: Jay
authors.initials: J
authors.lastname: Wright
authors.forename: Nupur
authors.initials: N
authors.lastname: Pande
authors.forename: Maureen
authors.initials: M
authors.lastname: Hoatlin
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011379:Prognosis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D045643:DNA Repair Enzymes