title: Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas.
abstract: OBJECTIVE
  A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.
  
  
  METHODS
  Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling.
  
  
  RESULTS
  Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition.
  
  
  CONCLUSIONS
  We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Craig
authors.initials: C
authors.lastname: Mermel
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Richard
authors.initials: R
authors.lastname: Tothill
authors.forename: Aikou
authors.initials: A
authors.lastname: Okamoto
authors.forename: Maria B
authors.initials: MB
authors.lastname: Raeder
authors.forename: Paul
authors.initials: P
authors.lastname: Harnett
authors.forename: Stephen
authors.initials: S
authors.lastname: Lade
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Anna V
authors.initials: AV
authors.lastname: Tinker
authors.forename: Bianca
authors.initials: B
authors.lastname: Locandro
authors.forename: Kathryn
authors.initials: K
authors.lastname: Alsop
authors.forename: Yoke-Eng
authors.initials: YE
authors.lastname: Chiew
authors.forename: Nadia
authors.initials: N
authors.lastname: Traficante
authors.forename: Sian
authors.initials: S
authors.lastname: Fereday
authors.forename: Daryl
authors.initials: D
authors.lastname: Johnson
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.forename: William
authors.initials: W
authors.lastname: Sellers
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Urashima
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019927:Cyclin E / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3