Michael J Worley1, Shubai Liu1, Yuanyuan Hua2, Jamie Sui-Lam Kwok3, Anicka Samuel1, Lei Hou1, Melina Shoni1, Shi Lu1, Evelien M Sandberg1, Anna Keryan1, Di Wu4, Shu-Kay Ng5, Winston P Kuo6, Carlos E Parra-Herran7, Stephen K W Tsui3, William Welch7, Christopher Crum7, Ross S Berkowitz1, Shu-Wing Ng8. 1. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 2. 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. 3. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. 4. Statistics Department, Harvard University, Boston, MA, USA. 5. School of Medicine, Griffith University, Meadowbrook, Australia. 6. Harvard Catalyst Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, MA, USA. 7. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 8. 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.
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.
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.
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