Epigenetic inactivation of 14-3-3 sigma in oral carcinoma: association with p16(INK4a) silencing and human papillomavirus negativity.
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.
Gasco
Milena
M
UO Oncologia Medica, Azienda Ospedaliera S Croce e Carle, 12100 Cuneo, Italy.
Bell
Alexandra K
AK
Heath
Victoria
V
Sullivan
Alex
A
Smith
Paul
P
Hiller
Louise
L
Yulug
Isik
I
Numico
Gianmauro
G
Merlano
Marco
M
Farrell
Paul J
PJ
Tavassoli
Mahvash
M
Gusterson
Barry
B
Crook
Tim
T
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
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