PTCH gene mutations in odontogenic keratocysts

An odontogenic keratocyst (OKC) is a benign cystic lesion of the jaws that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Recently, the gene for NBCCS was cloned and shown to be the human homologue of the Drosophila segment polarity gene Patched (PTCH), a tumor suppressor gene. The PTCH gene encodes a transmembrane protein that acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues, including tooth. We investigated three cases of sporadic odontogenic keratocysts and three other cases associated with NBCCS, looking for mutations of the PTCH gene. Non-radioactive single-strand conformational polymorphism and direct sequencing of PCR products revealed a deletion of 5 base pairs (bp) in exon 3 (518delAAGCG) in one sporadic cyst as well as mutations in two cysts associated with NBCCS, a nonsense (C2760A) and a missense (G3499A) alteration. This report is the first to describe a somatic mutation of PTCH in sporadic odontogenic keratocysts as well as two novel mutations in cysts associated with NBCCS, indicating a similar pathogenesis in a subset of sporadic keratocysts.     

Investigation of chromosome 9q22.3-q31 DNA marker loss in odontogenic keratocysts

Multiple basal cell carcinomas and odontogenic keratocysts of the jaws are a feature of the inherited naevoid basal cell carcinoma syndrome (NBCCS), although both occur more commonly as single, sporadic cases. The NBCCS gene has been mapped to chromosome 9q22.3-q31 and loss of heterozygosity for DNA markers from this region has been observed in familial and sporadic basal cell carcinomas. Based on these observations, we undertook a pilot study to determine if a similar pattern of chromosome loss occurs in odontogenic keratocysts. DNA extracted from microdissected odontogenic keratocyst epithelium was examined for loss of heterozygosity for six polymorphic DNA markers mapping to human chromosome 9q22.3-q31. Allelotype loss was detected in epithelium from three, single, sporadic odontogenic keratocysts. These results implicate homozygous inactivation of the NBCCS gene in the initiation and progression of the odontogenic keratocyst.     

牙源性囊肿上皮增殖活性的研究

目的：研究牙源性角化囊肿,含牙囊肿,根尖囊肿3种主要的牙源性囊肿衬里上皮的细胞增殖活性,方法：应用Ki-67单克隆抗体免疫组化LSAB法对30例牙源性囊肿进行免疫组化染色,结果通过计算机图像分析,计算单位面积衬里上皮内（mm2)阳性细胞数,进行统计学分析,结果：牙源性角化囊肿衬里上皮有较多的Ki-67阳性细胞,明显高于含牙囊肿和根尖囊肿;正常口腔粘膜未见Ki-67阳性表达,结论：Ki-67在不同的牙源性囊肿中表达的差异显示了它们具有不同的增殖和分化过程。     

p53 and MDM2 expression in odontogenic cysts and tumours

OBJECTIVE: The aim of this report was to assess p53 and MDM2 expression in odontogenic cysts and tumours, as they are known to play important roles in cell proliferation and tumorigenesis. MATERIALS AND METHODS: The expression of p53 and MDM2 proteins was determined immunohistochemically in 51 formalin-fixed, paraffin embedded specimens of odontogenic cysts and tumours.RESULTS: No positivity to p53 was found in the cases studied. MDM2 expression in ameloblastoma was higher than in radicular cysts, but lower than that observed in odontogenic keratocysts. No difference was observed between MDM2 expression in radicular cyst and adenomatoid odontogenic tumour. The clear-cell odontogenic ameloblastoma presented strong immunoreaction to this antigen.CONCLUSIONS: The results suggest that MDM2 overexpression may be involved in the pathogenesis of some odontogenic lesions.     

PTCH1 and SMO gene alterations in keratocystic odontogenic tumors

Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive jaw lesions that may occur in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations in the PTCH1 (PTCH) gene are responsible for NBCCS and are related in tumors associated with this syndrome. Mutations in the SMO gene have been identified in basal cell carcinoma and in medulloblastoma, both of which are features of NBCCS. To clarify the role of PTCH1 and SMO in KCOTs, we undertook mutational analysis of PTCH1 and SMO in 20 sporadic and 10 NBCCS-associated KCOTs, and for SMO, 20 additional cases of KCOTs with known PTCH1 status were also included. Eleven novel (1 of which occurred twice) and 5 known PTCH1 mutations were identified. However, no pathogenic mutation was detected in SMO. Our findings suggest that mutations are rare in SMO, but frequent in PTCH1 in sporadic and NBCCS-associated KCOTs. Abbreviations: NBCCS, nevoid basal cell carcinoma syndrome; KCOTs, keratocystic odontogenic tumors; BCCs, basal cell carcinomas.     

The odontogenic keratocyst and its occurrence in the nevoid basal cell carcinoma syndrome

There are histologic differences between odontogenic keratocysts occurring in the basal cell carcinoma syndrome (NBCCS) and as single lesions in otherwise healthy persons. This study identifies certain differences in age, gender, and site between the two groups. The age at removal of the first keratocyst is significantly lower in the syndrome group. On more thorough examination, patients with multiple keratocysts (excluding recurrences) are found to have other features of NBCCS. The term multiple cysts refers to the lifetime history of the patient and does not necessarily imply that more than one cyst is present at any one time.     

Imaging modality correlations of an odontogenic keratocyst in the nevoid basal cell carcinoma syndrome: a family case report

Multiple maxillary and mandibular cysts are principle features of nevoid basal cell carcinoma syndrome (NBCCS; Gorlin-Goltz syndrome). We present a family case report of NBCCS with odontogenic keratocyst where the findings on plain films, CT, clinical, and histopathologic examinations are compared and analyzed. The systemic manifestations included frontal bossing, odontogenic keratocyst, ectopic calcification in 1 patient, and bifid rib in 1 patient. CT examination displayed aspects of bone morphology not visible on the plain films. Odontogenic keratocyst diagnosis was confirmed by histopathological examination. The features identified by these combined clinical, imaging, and histologic findings are helpful in identifying an NBCCS patient, distinguishing keratocyst from others cysts or neoplasic lesions, and can therefore influence surgical management. NBCCS is a rare autosomal dominant cancer predisposition syndrome, which is important to recognize when a patient has multiple odontogenic keratocysts, because lifelong monitoring is essential for patient management.     

PCR-SSCP和DNA测序检测牙源性角化囊肿中PTCH基因的突变

目的 检测牙源性角化囊肿（OKC）中PTCH基因突变的特点。方法 采用PCR-SSCP筛查与DNA直接测序的方法对12例OKC进行PTCH基因突变的检测, 其中2例为痣样基底细胞癌综合征（NBCCS）相关OKC,10例为散发OKC。 结果 在4例OKC中发现了4处突变,其中2处生殖细胞突变发生在2例NBCCS相关OKC,2处体细胞突变发生在2例散发OKC。另外,还在10例OKC中检测到了8处PTCH基因多态性。结论 NBCCS相关OKC和散发OKC均可发生PTCH基因突变,但突变水平不同,PTCH基因的突变在二者的发病中可能均起重要作用。     

The Prevalence of EBV and KSHV in Odontogenic Lesions

ObjectivesOdontogenic lesions evolve as a result of altered dental development. This study aimed to evaluate the prevalence and the coinfection of Epstein-Barr virus (EBV) and Kaposi sarcoma–associated herpesvirus (KSHV) in radicular cysts, dentigerous cysts, odontogenic keratocysts, and ameloblastomas.MethodsPolymerase chain reaction (PCR) was used to analyse 66 cases of odontogenic lesions for the presence of EBV-DNA and KSHV-DNA. These lesions were 15 radicular cysts, 16 dentigerous cysts, 18 odontogenic keratocysts, and 17 ameloblastomas.ResultsEBV-DNA was detected in 24 (36.4%) of the studied samples as follows: 6 samples (40.0%) of radicular cysts, 4 (25.0%) of dentigerous cysts, 10 (55.6 %) of odontogenic keratocysts, and 4 (23.5%) of ameloblastomas (P = .168). KSHV-DNA was found in 16 (24.2%) of the studied samples as follows: 1 sample (6.7%) of radicular cysts, 6 (37.5%) of dentigerous cysts, 8 (44.4 %) of odontogenic keratocysts, and 1 (5.9%) of ameloblastomas (P = .001). Additionally, EBV and KSHV were positively correlated in all studied samples (P = .002).ConclusionsBoth EBV and KSHV are found in odontogenic cysts and ameloblastomas. KSHV and EBV are more prevalent in odontogenic keratocysts than in other studied odontogenic lesions. Further, there is a high prevalence of EBV and KSHV coinfection in odontogenic cysts and ameloblastomas.     

Calretinin expression in odontogenic cysts

Calretinin is a calcium-binding protein with a possible role as a calcium buffer, calcium-sensor, or regulator of apoptosis. Calretinin is expressed in neural tissue, is a specific marker of mesothelial cells, and has been demonstrated in the odontogenic epithelium during odontogenesis in rat molar tooth germs. Moreover, it has been found to be expressed in a high proportion of solid, unicystic, and multicystic ameloblastomas, whereas, on the contrary, no positive staining has been found in odontogenic keratocysts, residual cysts, and dentigerous cysts. The purpose of this study was to evaluate calretinin expression in radicular cysts, follicular cysts, orthokeratinized keratocysts, and parakeratinized keratocysts. A total of 70 odontogenic cysts, 24 radicular cysts, 24 follicular cysts, and 22 odontogenic keratocysts (10 orthokeratinized keratocysts, 12 parakeratinized keratocysts) were evaluated. All the radicular cysts, follicular cysts, and orthokeratinized keratocysts were negative. However in 8 of 12 parakeratinized keratocysts, there was a positivity to calretinin in the parabasal-intermediate layers of the cyst epithelium. This positivity to calretinin in the parabasal layers in parakeratinized keratocysts, similar to that found for other markers like PCNA and p53, could point to an abnormal control of the cell cycle and could help to explain the differences in the clinical and pathologic behavior of odontogenic keratocysts, in particular the differences found between orthokeratinized keratocysts and parakeratinized keratocysts.     

Blood group antigens A and B in ameloblastomas, odontogenic keratocysts and non-keratinizing cysts

abstract — The expression of blood group antigens A and B has been studied in 8 ameloblastomas, 16 odontogenic keratocysts from patients with basal cell nevus syndrome, 11 odontogenic keratocysts from patients without the syndrome, and 12 non-keratinizing odontogenic cysts, using a double layer immunofluorescence staining technique. The amount of antigen in the lesions was compared with the content of antigen in normal buccal mucosa from each patient. All ameloblastomas reacted negatively, three cysts from the patients with the basal cell nevus syndrome reacted negatively, and the odontogenic keratocysts from patients without the syndrome as well as the non-keratinizing odontogenic cysts all gave a positive reaction.     

Familial multiple odontogenic keratocysts

Multiple odontogenic keratocysts (OKCs) are principle features of nevoid basal cell carcinoma syndrome (NBCCS; Gorlin-Goltz syndrome). NBCCS is a genetic disorder transmitted by an autosomal dominant gene with variable expressivity, which is important to recognize when a patient has multiple OKCs. The cysts of the jaws are among the most common findings. Another feature is a certain appearance of the face, such as: large calvaria, high-arched eyebrows, broad nasal root, and mild hypertelorism. Before-therapy diagnosis is, therefore, as important as after-therapy diagnosis. Genetic counseling and examination may also be indicated. The purpose of this paper was to present a family case report of nevoid basal cell carcinoma syndrome with multiple odontogenic keratocysts. The features identified by these combined clinical, imaging, and histologic findings are described, along with a brief mention of the family history and a review of the literature.     

Expression of cell cycle and apoptosis-related proteins in sporadic odontogenic keratocysts and odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome.

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.     

Cytokeratin expression patterns for distinction of odontogenic keratocysts from dentigerous and radicular cysts

BACKGROUND: The clinical outcome of treatment of odontogenic cysts differs depending on separate entities. Particular clinical relevance must be attached to the distinction between odontogenic keratocysts, which have an evident tendency to recur, and other odontogenic cysts. The aim of this study was to evaluate cytokeratin (CK) expression patterns as an additional tool for characterization of different cysts as the histomorphologic appearance often is not decisive. METHODS: Thirty cases of dentigerous and radicular cysts respectively as well as 15 cases of odontogenic keratocysts were considered. Expression of CK 5/6, 7, 10, 13, 17, 19 and 20 was determined in addition to Ki-67 immunohistochemically. RESULTS: Expression of CK 17 was discernible in 93.3% of the odontogenic keratocysts, but only in 35.0% of dentigerous and radicular cysts under study (P < 0.001). CK 19 could be detected in 48.3% of dentigerous and radicular cysts, whereas odontogenic keratocysts were completely negative (P < 0.002). CONCLUSION: Immunohistochemical detection of CK 17 and 19 seems to be a valuable additional parameter distinguishing between odontogenic keratocysts and other odontogenic--especially dentigerous--cysts which clinically are likely the most significant differential diagnoses in this context. J Oral Pathol Med (2005) 34: 558-64.     

A comparative histological study of odontogenic keratocysts in basal cell naevus syndrome and control patients

164 odontogenic keratocysts from 60 patients with the basal cell naevus syndrome were compared with a similar number of single keratocysts matched for age and site. Significant differences between the two groups were found in the numbers of satellite cysts, solid islands of epithelial proliferation and odontogenic rests within the capsule, and in the numbers of mitotic figures in the epithelium lining the main cavity. An index of activity derived from these parameters suggests a greater growth potential in syndrome cysts; in addition, the patterns of association of the features support the theory that the odontogenic rests give rise to satellite cysts.     

A comparative histological study of odontogenic keratocysts in basal cell naevus syndrome and control patients

164 odontogenic keratocysts from 60 patients with the basal cell naevus syndrome were compared with a similar number of single keratocysts matched for age and site. Significant differences between the two groups were found in the numbers of satellite cysts, solid islands of epithelial proliferation and odontogenic rests within the capsule, and in the numbers of mitotic figures in the epithelium lining the main cavity. An index of activity derived from these parameters suggests a greater growth potential in syndrome cysts; in addition, the patterns of association of the features support the theory that the odontogenic rests give rise to satellite cysts.     

Analysis of the neoplastic nature and biological potential of sporadic and nevoid basal cell carcinoma syndrome-associated keratocystic odontogenic tumor

BACKGROUND: Keratocystic odontogenic tumor (KCOT), also known as odontogenic keratocyst, is a benign cystic neoplasm, which may be associated with nevoid basal cell carcinoma syndrome (NBCCS) and if it does, will occur as multiple cystic lesions. KCOT is locally destructive despite its bland histological features. However, the neoplastic nature of KCOT is not well established. Heparanase is an endo-d-glucuronidase enzyme that specifically cleaves heparan sulfate (HS) and the increase of its level in tumors promotes invasion, angiogenesis, and metastasis. METHODS: To investigate the neoplastic character of KCOT, we studied the localization patterns of heparanase in KCOT, focusing on the differences between sporadic and NBCCS-associated KCOTs, by immunohistochemistry and in situ hybridization. To compare the expression pattern of these cysts with non-tumorous odontogenic developmental cyst, dentigerous cyst was included. RESULTS: All the odontogenic cysts showed positive immunoreaction for heparanase protein in various intensities. The expression pattern of heparanase gene corresponded to that of protein expression. Interestingly, intense gene and protein expressions were observed in KCOT associated with NBCCS compared with sporadic ones and dentigerous cyst. CONCLUSIONS: The results implied that heparanase expression may be correlated with the neoplastic properties of KCOT, particularly in NBCCS-associated cases.     

PTCH gene altered in dentigerous cysts

Motivated by the evidence that odontogenic keratocysts are associated with genetic alterations, we examined the possibility that development of other odontogenic cysts can be attributed to gene malfunctioning, in particular to the PTCH gene. Cyst epithelium was examined for polymorphism on chromosome 9q22.3, the region that contains the PTCH gene. Loss of heterozygosity (LOH) for the D9S287 marker and/or D9S180 marker was observed in about 50% of dentigerous cysts, whereas radicular cysts gave no indication of lesions in the PTCH region. As a more direct argument for PTCH involvement in cystic growth, we report evidence of PTCH expression in dentigerous cyst lining, which indicates malfunctioning of the relevant signaling pathway. While we found no reason to believe that PTCH should be associated with radicular cysts, other genes may be implicated in their development. We performed immunohistochemical comparisons of keratocysts, dentigerous and radicular cysts for the nonmetastatic marker Nm23. A graded response placed radicular cysts in between the other two types, suggesting a similar neoplastic character for their epithelial proliferation.     

Comparison of radiographic and MRI features of a root-diverging odontogenic myxoma,with discussion of the differential diagnosis of lesions likely to move roots

Lesions that can produce divergence of the roots of teeth in the mandible include odontogenic cysts (odontogenic keratocysts, lateral periodontal cysts and radicular cysts), ameloblastomas, odontogenic myxomas, central giant cell granulomas, adenomatoid odontogenic tumors and aneurismal bone cysts, and other tumors. Moreover most benign jaw lesions can do this occasionally. However, when lesions--which show interradicular tear-shaped radiolucencies--are small it is often difficult to interpret them radiographically, because they do not show characteristic radiographic features. We describe a comparison of radiographic and magnetic resonance (MR) features of a root-diverging odontogenic myxoma, with discussion of the differential diagnosis of lesions likely to move roots. In addition, we discuss radiographic and MR features of possible lesions, which show similar radiographic findings to odontogenic myxoma.     

Immunolocalization of PTCH protein in odontogenic cysts and tumors

The human patched gene (PTCH) functions in both embryologic development and tumor suppression. PTCH mutations have been found in odontogenic keratocysts. However, the expression and localization of the protein product of the gene have not been determined in odontogenic tumors and cysts. We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas. All odontogenic lesions, including two keratocysts with truncating mutations, were positive for PTCH. Different types of lesions had different amounts of staining. Lack of staining was noted in the majority of basal cell carcinomas. Taken together, these data suggest that odontogenic keratocysts arise with heterozygous mutations of the PTCH gene.