title: Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer.
abstract: OBJECTIVE
  Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response.
  
  
  METHODS
  SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227).
  
  
  RESULTS
  We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26).
  
  
  CONCLUSIONS
  We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: evelyndespierre@gmail.com.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Moisse
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Betül
authors.initials: B
authors.lastname: Yesilyurt
authors.affiliation: Department of Gynecology, Campus Virchow-Klinikum, Charité University Hospital, European Competence Center for Ovarian Cancer Berlin, Germany.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Department of Gynecology, Campus Virchow-Klinikum, Charité University Hospital, European Competence Center for Ovarian Cancer Berlin, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.affiliation: Department of Gynecology, Hamburg-Eppendorf University Medical Center, University Cancer Center Hamburg-Eppendorf (UCCH), Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mahner
authors.affiliation: Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Austria.
authors.forename: Dan Cacsire
authors.initials: DC
authors.lastname: Castillo-Tong
authors.affiliation: Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.affiliation: Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moerman
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium; Vesalius Research Center, VIB, Leuven, Belgium. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds
keywords: High-resolution SNP array; Ovarian cancer; Platinum therapy; Predictive marker; Somatic copy number alteration