title: CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas.
abstract: The clinicopathological significance of amplification was investigated of the gene encoding cyclin E (CCNE1) and we assessed whether CCNE1 was a potential target in endometrioid endometrial carcinomas. CCNE1 amplification and CCNE1 or F-box and WD repeat domain-containing 7 (FBXW7) expression in endometrial endometrioid carcinoma was assessed by immunohistochemistry and fluorescence in situ hybridization. CCNE1 knockdown by small interfering RNA (siRNA) was used to assess the CCNE1 function. The results showed that CCNE1 amplification was present in 9 (8.3%) of 108 endometrial carcinomas. CCNE1 amplification was correlated with high histological grade (Grade 3; p=0.0087) and lymphovascular space invasion (p=0.0258). No significant association was observed between CCNE1 amplification and FIGO stage (p=0.851), lymph node metastasis (p=0.078), body mass index (p=0.265), deep myometrial invasion (p=0.256), menopausal status (p=0.289) or patient age (p=0.0817). CCNE1 amplification was significantly correlated with shorter progression-free and overall survival (p=0.0081 and 0.0073, respectively). CCNE1 protein expression or loss of FBXW7 expression in endometrial endometrioid carcinoma tended to be correlated with shorter progression-free and overall survival; however, this difference was not statistically significant. Multivariate analysis showed that CCNE1 amplification was an independent prognostic factor for overall survival but not for progression-free survival (P=0.0454 and 0.2175, respectively). Profound growth inhibition was observed in siRNA-transfected cancer cells with endogenous CCNE1 overexpression compared with that in cancer cells having low CCNE1 expression. CCNE1 amplification was independent of p53, HER2, MLH1 and ARID1A expression but dependent on PTEN expression in endometrial carcinomas. These findings indicated that CCNE1 amplification was critical for the survival of endometrial endometrioid carcinomas. Furthermore, the effects of CCNE1 knockdown were dependent on the CCNE1 expression status, suggesting that CCNE1-targeted therapy may be beneficial for patients with endometrial endometrioid carcinoma having CCNE1 amplification.
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Mohammed Tanjimur
authors.initials: MT
authors.lastname: Rahman
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Munmun
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Organ Pathology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ishikawa
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D019927:Cyclin E / Q000235:genetics*; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C112476:ARID1A protein, human; C475820:CCNE1 protein, human; C513273:FBXW7 protein, human; C501486:MLH1 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human