title: Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer.
abstract: Gene silencing associated with aberrant DNA methylation of promoter CpG islands is one mechanism through which several genes may be inactivated in human cancers. Cyclin D2, a member of the D-type cyclins, implicated in cell cycle regulation, differentiation and malignant transformation, is inactivated due to aberrant DNA methylation in several human cancers. In the present study, we examined the promoter methylation status and expression of Cyclin D2 in human epithelial ovarian cancer, and then determined the relationship between methylation status and various clinicopathological variables. Twelve ovarian cancer cell lines and 71 surgical specimens were examined by methylation-specific polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction to evaluate the methylation status and expression of the Cyclin D2 gene. The relationship between methylation status and various clinicopathological variables was evaluated using statistical analysis. Aberrant methylation of Cyclin D2 was present in five of 12 ovarian cancer cell lines and 16 of 71 primary ovarian cancer tissues. In five cell lines with methylation, expression of the Cyclin D2 gene tended to be lower than in cell lines without methylation. In ovarian cancer tissues, methylation bands were detected in 16 of 71 cases. The methylation status of Cyclin D2 was associated with advanced stage and a residual tumor size (>2 cm) (P = 0.027 and P = 0.031, respectively). Based on univariate analysis, patients with aberrant methylation of the Cyclin D2 promoter had a significantly worse chance of disease-free survival than those without methylation (P = 0.021). Our results suggest that aberrant promoter methylation of the Cyclin D2 gene is significantly associated with patient prognosis in epithelial ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University, Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku Sendai, 980-8574 Japan. msakuma@mail.tains.tohoku.ac.jp
authors.forename: Michiko
authors.initials: M
authors.lastname: Sakuma
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Akahira
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ito
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niikura
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Okamura
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine