title: Coincident inactivation of 14-3-3sigma and p16INK4a is an early event in vulval squamous neoplasia.
abstract: The structure and expression of 14-3-3 sigma(sigma) was analysed in squamous carcinomas (SCC) of the vulva and in the vulval pre-malignant lesion vulval intraepithelial neoplasia (VIN). Sequence analysis of the sigma coding region did not detect mutations in any case of SCC or VIN III and loss of heterozygosity (LOH) occurred in only 2 out of 27 informative cases. In contrast to the absence of genetic change, methylation-specific PCR (MSP) analysis revealed dense CpG methylation within the sigma gene in approximately 60% of cases of vulval SCC, but methylation was not detected in matched, normal epithelial tissue. Methylation was associated in all cases with reduced or absent expression of sigma mRNA. There was no correlation between sigma methylation and HPV or p53 status. Analysis of pre-malignant vulval intraepithelial neoplasia (VIN) revealed that sigma methylation was detectable early in neoplastic development. Co-incident methylation, accompanied by loss of expression, of sigma and p16INK4a was commonly detected in both SCC and VIN III, suggesting that epigenetic silencing of these two genes is an early and important event in vulval neoplasia.
authors.affiliation: UO Oncologia Medica, Azienda Ospedaliera S Croce e Carle, Via Coppino 26, 12100 Cuneo, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Alex
authors.initials: A
authors.lastname: Sullivan
authors.forename: Claire
authors.initials: C
authors.lastname: Repellin
authors.forename: Louise
authors.initials: L
authors.lastname: Brooks
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Farrell
authors.forename: John A
authors.initials: JA
authors.lastname: Tidy
authors.forename: Barbara
authors.initials: B
authors.lastname: Dunne
authors.forename: Barry
authors.initials: B
authors.lastname: Gusterson
authors.forename: David J
authors.initials: DJ
authors.lastname: Evans
authors.forename: Tim
authors.initials: T
authors.lastname: Crook
mesh_terms: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D005092:Exonucleases; D005095:Exoribonucleases; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D019656:Loss of Heterozygosity; D009363:Neoplasm Proteins; D027383:Papillomaviridae / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014846:Vulvar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human