title: Epigenetic inactivation of 14-3-3 sigma in oral carcinoma: association with p16(INK4a) silencing and human papillomavirus negativity.
abstract: In vitro studies have identified 14-3-3sigma as a regulator of senescence in human keratinocytes. To assess its contribution to squamous neoplasia, we have analyzed genetic and epigenetic changes in this gene in squamous cell carcinomas (SCCs) and dysplastic lesions of the oral cavity. No mutations were detected in the coding sequence of 14-3-3sigma in 20 oral carcinomas, and there was loss of heterozygosity in only 7 of 40 informative cases. In contrast to the absence of genetic change, aberrant methylation within 14-3-3sigma was detected in 32 of 92 squamous cell carcinomas and in 3 of 6 oral dysplasias and was associated with reduced or absent expression at both mRNA and protein levels. Methylation was not detected in matched, normal epithelial tissue controls. Carcinomas in which 14-3-3sigma was methylated were significantly more likely to lack DNA sequences from human papillomavirus and to have coincident methylation of p16(INK4a) than cases that expressed 14-3-3sigma. Methylation was detected in SCC, both wild-type and mutant for p53, but was more commonly detected in cancers with wild-type p53. These results implicate coincident epigenetic abrogation of function in both sigma and p16(INK4a) in a subset of SCCs of the oral cavity.
authors.affiliation: UO Oncologia Medica, Azienda Ospedaliera S Croce e Carle, 12100 Cuneo, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Bell
authors.forename: Victoria
authors.initials: V
authors.lastname: Heath
authors.forename: Alex
authors.initials: A
authors.lastname: Sullivan
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Isik
authors.initials: I
authors.lastname: Yulug
authors.forename: Gianmauro
authors.initials: G
authors.lastname: Numico
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Farrell
authors.forename: Mahvash
authors.initials: M
authors.lastname: Tavassoli
authors.forename: Barry
authors.initials: B
authors.lastname: Gusterson
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 / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation; D004279:DNA, Viral / Q000032:analysis; D005092:Exonucleases; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D009154:Mutation; D009363:Neoplasm Proteins; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014412:Tumor Virus Infections / Q000150:complications / Q000821:virology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D009363:Neoplasm Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human