title: POSTN/TGFBI-associated stromal signature predicts poor prognosis in serous epithelial ovarian cancer.
abstract: OBJECTIVE
  To identify molecular prognosticators and therapeutic targets for high-grade serous epithelial ovarian cancers (EOCs) using genetic analyses driven by biologic features of EOC pathogenesis.
  
  
  METHODS
  Ovarian tissue samples (n = 172; 122 serous EOCs, 30 other EOCs, 20 normal/benign) collected prospectively from sequential patients undergoing gynecologic surgery were analyzed using RNA expression microarrays. Samples were classified based on expression of genes with potential relevance in ovarian cancer. Gene sets were defined using Rosetta Similarity Search Tool (ROAST) and analysis of variance (ANOVA). Gene copy number variations were identified by array comparative genomic hybridization.
  
  
  RESULTS
  No distinct subgroups of EOC could be identified by unsupervised clustering, however, analyses based on genes correlated with periostin (POSTN) and estrogen receptor-alpha (ESR1) yielded distinct subgroups. When 95 high-grade serous EOCs were grouped by genes based on ANOVA comparing ESR1/WT1 and POSTN/TGFBI samples, overall survival (OS) was significantly shorter for 43 patients with tumors expressing genes associated with POSTN/TGFBI compared to 52 patients with tumors expressing genes associated with ESR1/WT1 (median 30 versus 49 months, respectively; P = 0.022). Several targets with therapeutic potential were identified within each subgroup. BRCA germline mutations were more frequent in the ESR1/WT1 subgroup. Proliferation-associated genes and TP53 status (mutated or wild-type) did not correlate with survival. Findings were validated using independent ovarian cancer datasets.
  
  
  CONCLUSIONS
  Two distinct molecular subgroups of high-grade serous EOCs based on POSTN/TGFBI and ESR1/WT1 expressions were identified with significantly different OS. Specific differentially expressed genes between these subgroups provide potential prognostic and therapeutic targets.
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: Beth.Karlan@cshs.org.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.affiliation: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lester
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Anderson
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Ginther
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Marlena
authors.initials: M
authors.lastname: Fejzo
authors.affiliation: Division of Hematology/Oncology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Slamon
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C512835:POSTN protein, human
keywords: Molecular profiling; Ovarian cancer; Tumor microenvironment