title: Improved classification of epithelial ovarian cancer: results of 3 danish cohorts.
abstract: OBJECTIVE
  An increasing body of evidence has suggested that epithelial ovarian cancer (EOC) patients can broadly be divided into 2 groups on the basis of histopathologic parameters and molecular profiles. Type 1 tumors are slow-growing tumors with inherent mutations such as KRAS or BRAF mutations, whereas type 2 tumors are more rapidly growing tumors of which many contain TP53 mutations. In the present study, we performed a comprehensive study in a large Danish material to evaluate the clinical importance.
  
  
  METHODS
  A total of 512 tissue samples were included (430 EOCs, 34 borderline, 28 benign tumors, and 20 normal ovaries). KRAS mutations (codon 12/13) and BRAF codon 600 mutations were analyzed from formalin-fixed paraffin-embedded tissue by ARMS qPCR. p53 expression was examined by immunohistochemistry.
  
  
  RESULTS
  Of the EOC patients, 25% had histopathologically classified type 1 tumors, and of these, 44% were either KRAS or BRAF mutated. Of patients with histopathologic type 2 tumors, 66% showed p53 protein overexpression, whereas 4 (1.5%) patients contained a KRAS mutation. In a univariate survival analysis, a large difference in survival was seen between patients with type 1 and type 2 tumors. Patients with type histologic 2 tumors had significantly worse survival compared with patients with type 1 tumors (P < 10). International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, residual tumor, and KRAS/BRAF mutation were independent predictors of overall survival in the multivariate analysis. Patients with KRAS/BRAF mutated carcinomas showed independent decreased overall survival with a hazard ratio of 2.01 (95% confidence interval, 1.13-3.57; P = 0.018).
  
  
  CONCLUSIONS
  KRAS/BRAF mutations are with very few exceptions constrained to patients with histopathologic type 1 tumors, whereas p53 overexpression is very frequent in type 2 tumors. KRAS/BRAF mutations had independent prognostic importance. The classification presented here should have a major therapeutic implication and serve as a hallmark of future clinical trials.
authors.affiliation: Department of Oncology, Vejle Hospital, Vejle, Denmark. Karina.Dahl.Steffensen@slb.regionsyddanmark.dk
authors.forename: Karina Dahl
authors.initials: KD
authors.lastname: Steffensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Waldstrøm
authors.forename: Anni
authors.initials: A
authors.lastname: Grove
authors.forename: Bente
authors.initials: B
authors.lastname: Lund
authors.forename: Niels
authors.initials: N
authors.lastname: Pallisgård
authors.forename: Anders
authors.initials: A
authors.lastname: Jakobsen
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D003062:Codon; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D011905:Genes, ras; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016612:Paraffin Embedding; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D003062:Codon; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf