title: Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.
abstract: OBJECTIVE
  To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC).
  
  
  METHODS
  51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation.
  
  
  RESULTS
  Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression.
  
  
  CONCLUSIONS
  Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.
authors.affiliation: Radiation Oncology Department, Duke University Medical Center, United States.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Siamakpour-Reihani
authors.affiliation: Duke Department of Biostatistics and Bioinformatics, Duke University Medical Center, United States; Bioinformatics Shared Resource, Duke Cancer Institute, United States.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Bioinformatics Shared Resource, Duke Cancer Institute, United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Taylor
authors.initials: T
authors.lastname: Turner
authors.affiliation: Duke Department of Biostatistics and Bioinformatics, Duke University Medical Center, United States.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pathology, Duke University Medical Center, United States.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Bean
authors.affiliation: Radiation Oncology Department, Duke University Medical Center, United States.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Horton
authors.affiliation: Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Department of Surgery, Duke University Medical Center, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.affiliation: Radiation Oncology Department, Duke University Medical Center, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: angeles.secord@dm.duke.edu.
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez Secord
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D014408:Biomarkers, Tumor / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D000071063:Endoglin; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011956:Receptors, Cell Surface / Q000032:analysis; D015996:Survival Rate
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C064206:ENG protein, human; D000071063:Endoglin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface
keywords: Angiogenesis; Biomarkers; Gene expression; High-grade serous ovarian carcinoma; Overall survival