Abstract
Keratocystic odontogenic tumor (KCOT) arises as part of Gorlin syndrome (GS) or as a sporadic lesion. Gene mutations and loss of heterozygosity (LOH) of the hedgehog receptor PTCH1 plays an essential role in the pathogenesis of KCOT. However, some KCOT cases lack evidence for gene alteration of PTCH1, suggesting that other genes in the hedgehog pathway may be affected. PTCH2 and SUFU participate in the occurrence of GS-associated tumors, but their roles in KCOT development are unknown. To elucidate the roles of these genes, we enrolled 36 KCOT patients in a study to sequence their entire coding regions of PTCH1, PTCH2 and SUFU. LOH and immunohistochemical expression of these genes, as well as the downstream targets of hedgehog signaling, were examined using surgically-excised KCOT tissues. PTCH1 mutations, including four novel ones, were found in 9 hereditary KCOT patients, but not in sporadic KCOT patients. A pathogenic mutation of PTCH2 or SUFU was not found in any patients. LOH at PTCH1 and SUFU loci correlated with the presence of epithelial budding. KCOT harboring a germline mutation (Type 1) showed nuclear localization of GLI2 and frequent histological findings such as budding and epithelial islands, as well as the highest recurrence rate. KCOT with LOH but without a germline mutation (Type 2) less frequently showed these histological features, and the recurrence rate was lower. KCOT with neither germline mutation nor LOH (Type 3) consisted of two subgroups, Type 3A and 3B, which were characterized by nuclear and cytoplasmic GLI2 localization, respectively. Type 3B rarely exhibited budding and recurrence, behaving as the most amicable entity. The expression patterns of CCND1 and BCL2 tended to correlate with these subgroups. Our data indicates a significant role of PTCH1 and SUFU in the pathogenesis of KCOT, and the genotype-oriented subgroups constitute entities with different potential aggressiveness.
Highlights
Gorlin syndrome (GS) is a rare autosomal-dominant genetic disease, characterized by developmental disorders, such as falx cerebri calcification, palmoplantar pits and rib deformities
We have hypothesized the following: 1) PTCH2 and SUFU may be affected in GS patients who have no PTCH1 mutation; 2) sporadic Keratocystic odontogenic tumor (KCOT) patients may be predisposed to KCOT because of heterozygous germline mutations of PTCH1, PTCH2 or SUFU, whose phenotypes are too weak to present with any other symptoms; and 3) sporadic KCOT that has no alteration in PTCH1 locus may develop as a result of alterations in PTCH2 or SUFU locus
We engaged in mutational analysis of sporadic KCOT patients to check the hypothesis that they may be predisposed to KCOT because of germline mutations of PTCH1, PTCH2 or SUFU, whose phenotypes are too weak to present with any other symptoms
Summary
Gorlin syndrome (GS) is a rare autosomal-dominant genetic disease, characterized by developmental disorders, such as falx cerebri calcification, palmoplantar pits and rib deformities. Patients are predisposed to several neoplasms, including basal cell carcinoma (BCC), medulloblastoma and fibroma of ovary or heart [1,2]. Mutations in PTCH1, the homologue of drosophila segment polarity gene patched, have been found in GS patients, and this spectrum of neoplasms is thought to arise due to a malfunction of PTCH1 [3,4]. The Patched protein is a 12-pass transmembrane receptor of Hedgehog, and it behaves as a tumor suppressor [5]. Binding with Hedgehog relieves the inhibitory effect of Patched on the latent activity of Smoothened. This results in activation of the transcription factor cubitus interruptus (Ci), whose mammalian homologue is Gli, which mediates the hedgehog target gene expression [6]. Gli regulates a broad range of downstream gene targets such as PTCH1, Cyclin D (CCND), BCL2 and FOXM1 [7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
