title: CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis.
abstract: Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms.
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan.|Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.|Department of Molecular Pathology, Hiroshima University School of Medicine, Hiroshima, Japan.
authors: Ayse
authors: A
authors: Ayhan
authors: Pathology Unit, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors: Elisabetta
authors: E
authors: Kuhn
authors: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors: Ren-Chin
authors: RC
authors: Wu
authors: Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan.
authors: Hiroshi
authors: H
authors: Ogawa
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: Asli
authors: A
authors: Bahadirli-Talbott
authors: Department of Pathology, National Taiwan University College of Medicine, Taipei City, Taiwan.
authors: Tsui-Lien
authors: TL
authors: Mao
authors: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Haruhiko
authors: H
authors: Sugimura
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: Ie-Ming
authors: IM
authors: Shih
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: Tian-Li
authors: TL
authors: Wang
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C112476:ARID1A protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase