title: Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures.
abstract: BACKGROUND
  It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs.
  
  
  METHODS
  We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF).
  
  
  RESULTS
  We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p<0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype.
  
  
  CONCLUSIONS
  Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.
authors.affiliation: Department of Obstetrics/Gynecology & Women's Health, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: Habib
authors.initials: H
authors.lastname: Hamidi
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Department of Biostatistics, University of Kansas, Kansas City, KS, United States.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: Hsiao-Wang
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States.
authors.forename: William A
authors.initials: WA
authors.lastname: Cliby
authors.affiliation: Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: He-Jing
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Dowdy
authors.affiliation: Department of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States.
authors.forename: Bobbie S
authors.initials: BS
authors.lastname: Gostout
authors.affiliation: Department of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States. Electronic address: gkonecny@mednet.ucla.edu.
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome
keywords: Clear cell and high grade serous histologies; Endometrioid; Molecular subtypes; Ovarian cancer