cyclin-d1 and Basal-Cell-Nevus-Syndrome

Immunocytochemical studies of the expression of PCNA, Ki67 and p53 protein have been done by different groups on sporadic keratocysts (OKCs) and OKCs associated with the naevoid basal cell carcinoma syndrome (NBCCS). These 'markers' have in common that they are all expressed in actively proliferating cells, particularly in neoplasms. The findings were compared with their expression in dentigerous and radicular cysts. While there was some variability in the reported results, probably because of technical inconsistencies and the use of different antibodies, a definite trend emerged. In general PCNA, Ki67 and p53 positivity occurred more frequently and more intensely in the OKCs, and in the syndrome-related more than the solitary, compared with the other cyst types. In the OKCs the positivity was expressed mostly in the suprabasal layers of epithelium whereas in the other cysts types it was mainly in the basal layer that positivity was observed. Other studies showed that the gene for the NBCCS (PTCH), a tumour suppressor gene, mapped to chromosome 9q22.3. PTCH gene mutation has been shown to be an important step in the pathogenesis of the OKC and was thought to have a role in the development of the sporadic as well as the syndrome-related OKCs. The 'two-hits' hypothesis was invoked in support of the view that syndrome-related basal cell carcinomas (BCCs) and OKCs probably arise from precursor cells that contain an inherited 'first hit'. Only a single mutation was then required in the somatic cell to cause homozygous inactivation and neoplastic progression. Sporadic OKCs might arise from susceptible cells in which two somatic mutations or 'hits' have occurred, one of which manifests as allelic loss. The loss of tumour suppressor genes supports the view that the OKC is a benign neoplasm.

Topics: Basal Cell Nevus Syndrome; Cell Division; Cyclin D1; Humans; Immunohistochemistry; Ki-67 Antigen; Mutation; Odontogenic Cysts; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities and a predisposition to cancers. Although multiple jaw tumors, such as keratocystic odontogenic tumors (KCOTs), are one of the most frequent complications in NBCCS, the molecular mechanism for how KCOTs develop in NBCCS is poorly understood. A 15-year-old girl with 2 jaw tumors was diagnosed as NBCCS according to the clinical criteria. The pathologic findings indicated that the 2 tumors were consistent with KCOTs. A PTCH1 mutation, c.1472delT, was detected in her peripheral blood as well as in the 2 tumors. Interestingly, an additional PTCH1 mutation, c.264_265insAATA, that was not present in the peripheral blood, was found in the maxillary tumor but not the mandibular tumor. The Ki-67 labeling index was significantly higher in the maxillary KCOT (17.7%) than in the mandibular KCOT (14.3%). These findings indicate distinct molecular mechanisms of tumorigenesis in these KCOTs.

Topics: Adolescent; Basal Cell Nevus Syndrome; Cyclin D1; DNA Mutational Analysis; Female; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Mandibular Neoplasms; Maxillary Neoplasms; Odontogenic Tumors; Patched Receptors; Patched-1 Receptor; Receptors, Cell Surface

We examined the immunohistochemical expressions of cell-cycle- and apoptosis-related factors to investigate the possible role of these factors in odontogenic keratocyst (OKC). Expression of cyclin D1 and p16 protein was detected in the basal and parabasal cells in lining epithelium of OKCs and was found more frequently in basal cell nevus syndrome (BCNS)-associated OKCs than in primary or recurrent OKCs. Positivity for p21 protein was detected in basal to superficial cells, whereas that for p27 protein was detected in parabasal to superficial cells in lining epithelium of OKCs. DNA topoisomerase IIalpha reacted with nuclei in basal and parabasal cells of the lining epithelium of OKCs, and positive cells were observed in BCNS-associated OKCs significantly more frequently than in primary or recurrent OKCs. Expression of Fas in suprabasal to superficial cells and expression of Fas-L in basal and parabasal cells were detected in lining epithelium of OKCs. Immunoreactivity for caspase-3 was detected in basal to suprabasal or superficial cells in lining epithelium of OKCs. Single stranded (ss)DNA-positive nuclei were detected in superficial cells in lining epithelium of OKCs. Fas was more broadly distributed in BCNS-associated OKCs than in primary OKCs, and ssDNA-positive cells were observed in BCNS-associated OKCs significantly more frequently than in primary or recurrent OKCs. These results suggest that BCNS-associated OKCs might be a distinguishable entity from solitary OKCs.

Topics: Adult; Antibodies, Monoclonal; Antigens, Surface; Apoptosis; Basal Cell Nevus Syndrome; Caspase 3; Caspases; Cell Cycle Proteins; Cell Nucleus; Chi-Square Distribution; Coloring Agents; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA Topoisomerases, Type II; DNA, Single-Stranded; Enzyme Inhibitors; Enzyme Precursors; Epithelium; Fas Ligand Protein; fas Receptor; Female; Humans; Immunohistochemistry; Ligands; Male; Membrane Glycoproteins; Microfilament Proteins; Muscle Proteins; Odontogenic Cysts; Recurrence; Statistics, Nonparametric

Odontogenic keratocysts are occasionally (4-5%) associated with the nevoid basal cell carcinoma syndrome, a pleiotropic, autosomal disorder presenting a spectrum of developmental abnormalities and a predisposition for the development of different neoplasms. The aim of this study was to establish whether keratocysts showing clinically aggressive behavior associated with nevoid basal cell carcinoma syndrome reflect differences in cellular proliferation rate and/or in the expression of oncoproteins and tumor suppressor genes. For this reason, formalin-fixed paraffin-embedded sections of odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome (16 cases) and sporadic odontogenic keratocysts (16 cases) were compared for expression of proliferating cell nuclear antigen (PCNA) and p53, bcl-2, and bcl-1 (cyclin D1) onco-proteins. Most of the epithelial lining of odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome showed nuclear immunopositivity for p53 protein and overexpression of cyclin D1 with various degrees of staining intensity. All sporadic odontogenic keratocysts were negative for p53 and cyclin D1. The expressions of bcl-2 oncoprotein were found to be substantially similar between the two groups of lesions, with a cytoplasmic immunopositivity localized only in the resting reserve basal layer of the epithelium. PCNA expression showed no statistically significant difference between the two groups of lesions. In conclusion, the finding of cyclin D1 and p53 overexpression in odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome could be considered a hallmark of a mutated cellular phenotype, thus leading to the hypothesis that their aggressive clinical behavior could be due to a dysregulation of the expression of cyclin D1 and p53 proteins, involved in a check-point control of cellular proliferation.

Topics: Analysis of Variance; Apoptosis; Basal Cell Nevus Syndrome; Cell Cycle; Cell Division; Cell Nucleus; Cyclin D1; Cytoplasm; Epithelial Cells; Epithelium; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Mutation; Odontogenic Cysts; Oncogene Proteins; Phenotype; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53