title: Alterations of the p16/Rb/cyclin-D1 pathway in vulvar carcinoma, vulvar intraepithelial neoplasia, and lichen sclerosus.
abstract: Three different alterations in the p16/pRb/cyclin-D1 pathway (p16(INK4a)-promoter hypermethylation and expression of pRb and cyclin-D1) were investigated in a series of 38 cases of vulvar carcinoma (VC), 13 cases of vulvar intraepithelial neoplasia (VIN), and 21 cases of lichen sclerosus (LS). Paraffin blocks from 72 patients were selected for investigation of DNA methylation patterns in the CpG island of p16(INK4a) by methylation-specific polymerase chain reaction. Immunohistochemical studies for pRb and cyclin-D1 were performed using the standard avidin-biotin-peroxidase complex method. Epigenetic silencing of p16(INK4a) was detected in 68% of VC, 69.2% of VIN, and 42.8% of LS cases. Lack of pRb protein was found in 21% of VC, 0% of VIN, and 0% of LS cases. Overexpression of cyclin-D1 was found in 21% of VC, 30.8% of VIN, and 0% of LS cases. We conclude (1) that p16(INK4a) epigenetic inactivation most likely represents an early event, insufficient for malignant transformation, that may occur in clinically benign lesions such as LS; (2) that lack of pRb was only detected in fewer than one quarter of the carcinomas and could be considered a late secondary event; and (3) that cyclin-D1, which was overexpressed in VC and VIN, could contribute to the malignant transformation in association with p16 hypermethylation.
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lerma
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D018459:Lichen Sclerosus et Atrophicus / Q000378:metabolism* / Q000473:pathology; D008745:Methylation; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction / Q000379:methods; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014846:Vulvar Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004273:DNA, Neoplasm; D016160:Retinoblastoma Protein; D019938:Cyclin D1