title: Genomic analysis reveals the molecular heterogeneity of ovarian clear cell carcinomas.
abstract: OBJECTIVE
  Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist.
  
  
  METHODS
  Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test.
  
  
  RESULTS
  Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors.
  
  
  CONCLUSIONS
  OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs.
authors.affiliation: Department of Gynaecologic Oncology, Royal Marsden Hospital NHS Foundation Trust, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Royal Marsden Hospital, London, United Kingdom.
authors.forename: David S P
authors.initials: DS
authors.lastname: Tan
authors.forename: Marjan
authors.initials: M
authors.lastname: Iravani
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
authors.forename: Maryou B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: Fernanda
authors.initials: F
authors.lastname: Milanezi
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Charles
authors.initials: C
authors.lastname: Gourley
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Radost
authors.initials: R
authors.lastname: Vatcheva
authors.forename: Joanne
authors.initials: J
authors.lastname: Millar
authors.forename: Karen
authors.initials: K
authors.lastname: Thomas
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Alistair
authors.initials: A
authors.lastname: Williams
authors.forename: Charles
authors.initials: C
authors.lastname: Jameson
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005821:Genetic Techniques; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence; D015999:Multivariate Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D004247:DNA