title: Molecular changes in endometriosis-associated ovarian clear cell carcinoma.
abstract: BACKGROUND
  Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood.
  
  
  METHODS
  We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin-embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments.
  
  
  RESULTS
  PTEN was significantly lost in both endometriosis and invasive tumour tissues, while oestrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2 and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p ⩽ 0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodelling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker Wilms' tumour protein 1 (WT1) in OCCC, while endometriotic tissues showed significant co-expression of WT1 and ER.
  
  
  CONCLUSIONS
  Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic programme for lineage-specific transformation of endometriosis to OCCC.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Worley
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shubai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Obstetrics & Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Hua
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Jamie Sui-Lam
authors.initials: JS
authors.lastname: Kwok
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Anicka
authors.initials: A
authors.lastname: Samuel
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Shoni
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Lu
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Evelien M
authors.initials: EM
authors.lastname: Sandberg
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Keryan
authors.affiliation: Statistics Department, Harvard University, Boston, MA, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Medicine, Griffith University, Meadowbrook, Australia.
authors.forename: Shu-Kay
authors.initials: SK
authors.lastname: Ng
authors.affiliation: Harvard Catalyst Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, MA, USA.
authors.forename: Winston P
authors.initials: WP
authors.lastname: Kuo
authors.affiliation: Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Parra-Herran
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Stephen K W
authors.initials: SK
authors.lastname: Tsui
authors.affiliation: Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Welch
authors.affiliation: Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Crum
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: sng@partners.org.
authors.forename: Shu-Wing
authors.initials: SW
authors.lastname: Ng
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004715:Endometriosis / Q000150:complications*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor
keywords: Endometriosis; Epigenetic reprogramming; Gene expression; Ovarian clear cell carcinoma