title: Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.
abstract: Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.
authors.affiliation: Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M.H. Marigowda Road, Bangalore, 560029, India, rahulbhagat1234@gmail.com.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhagat
authors.forename: Sandeep Sriram
authors.initials: SS
authors.lastname: Kumar
authors.forename: Shilpa
authors.initials: S
authors.lastname: Vaderhobli
authors.forename: Chennagiri S
authors.initials: CS
authors.lastname: Premalata
authors.forename: Venkateshaiah Reddihalli
authors.initials: VR
authors.lastname: Pallavi
authors.forename: Gawari
authors.initials: G
authors.lastname: Ramesh
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnamoorthy
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000706:statistics & numerical data; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta