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Mechanisms of Inactivation of PTCH1 Gene in Nevoid Basal Cell Carcinoma Syndrome: Modification of the Two-Hit Hypothesis

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Mechanisms of Inactivation of PTCH1 Gene in Nevoid Basal Cell Carcinoma Syndrome: Modification of the Two-Hit Hypothesis Published OnlineFirst January 12, 2010; DOI: 10.1158/1078-0432.CCR-09-2574 Published Online First on January 12, 2010 as 10.1158/1078-0432.CCR-09-2574 Clinical Human Cancer Biology Cancer Research Mechanisms of Inactivation of PTCH1 Gene in Nevoid Basal Cell Carcinoma Syndrome: Modification of the Two-Hit Hypothesis Shuang Pan1,2, Qing Dong1, Li-Sha Sun1, and Tie-Jun Li1 Abstract Purpose: PTCH1 has been identified as the gene responsible for nevoid basal cell carcinoma syndrome (NBCCS). Keratocystic odontogenic tumors (KCOT) are aggressive jaw lesions that may occur in isolation or in association with NBCCS. The aim of this study was to investigate the genetic and/or epigenetic me- chanisms of inactivation of the PTCH1 gene in patients with NBCCS and related sporadic KCOTs. Experimental Design: Loss of heterozygosity was analyzed in 44 patients (15 NBCCS-related and 29 sporadic KCOTs), all of whom were previously analyzed for PTCH1 mutations. Allelic location was es- tablished in tumors carrying two coincident mutations. PTCH1 mRNA expression and promoter methyl- ation status were analyzed in a panel of KCOTs to define the possible role of epigenetic effects on PTCH1 inactivation. Results: Although mutations and loss of heterozygosity of PTCH1 were frequently detected in both syndromic and nonsyndromic cases, hypermethylation of the PTCH1 promoter was not identified in the present series. Of all the 44 cases examined, 13 were identified to fit the two-hit model, 14 to conform to a one-hit model, and the remaining 17 cases showing no alteration in PTCH1. The distribution of two- hit, one-hit, and non-hit cases was significantly different between syndrome and nonsyndrome patients (P < 0.02). Conclusions: This study indicates that PTCH1 gene alternation may play a significant role in the path- ogenesis of NBCCS and the related sporadic tumors. Not only the standard two-hit model, but also hap- loinsufficiency or dominant-negative isoforms may be implicated in the inactivation of the PTCH1 gene. Clin Cancer Res; 16(2); 442–50. ©2010 AACR. Nevoid basal cell carcinoma syndrome (NBCCS, also a key regulator of embryonic development and tumorigen- known as Gorlin syndrome, OMIM NO.109400) is a rare esis controlling cellular proliferation and fate. Misregula- autosomal dominant disorder (1) characterized by a spec- tion of the signaling caused by inactivation of PTCH1 trum of developmental defects and a predisposition to has been implicated in the development of NBCCS and a number of different neoplasms, such as basal cell carci- some related sporadic tumors, supporting the hypothesis nomas, keratocystic odontogenic tumors (KCOT), medul- that PTCH1 might act as a tumor suppressor gene in this loblastoma, ovarian fibroma, etc. (2). The human syndrome (4). homologue of the Drosophila segment polarity gene, According to Knudson's two-hit model of tumor sup- PTCH1 (OMIM NO.601309), has been identified as the pressor genes (5), two mutations, one occurring in each gene responsible for NBCCS as well as some related spo- of the two alleles of the gene, or one mutation in one tu- radic tumors (3). PTCH1 has been mapped to 9q22.3-31, mor suppressor gene allele accompanied by another allelic and consists of 23 exons spanning approximately 47 kb loss of the remaining wild-type allele, are required to trig- and encoding a 1447-amino acid transmembrane glyco- ger neoplasm formation. Tumors in NBCCS patients are protein. It is involved in the Hedgehog signaling pathway, believed to develop according to the two-hit hypothesis (6). The first hit in NBCCS is a germline mutation in the PTCH1 gene, and is followed by a second hit which is a Authors' Affiliations: 1Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China; and 2Department of somatic inactivating mutation or deletion. KCOTs are Endodontics, The First Affiliated Hospital of Harbin Medical University, common aggressive jaw cystic tumors with a high growth Harbin, China potential and a propensity for recurrence (7, 8), which Corresponding Author: Tie-Jun Li, Department of Oral Pathology, Pe- usually act as a feature of the inherited NBCCS. Like neo- king University, School and Hospital of Stomatology, 22 South Zhong- guancun Avenue, Haidian District, Beijing 100081, P. R. China. Phone: plasms in cancer predisposition syndromes, KCOTs in 8610-62179977, ext. 2203; Fax: 8610-62173402; E-mail: litiejun22@vip. NBCCS are multiple and appear in a random pattern, sina.com. but similar isolated defects are seen occasionally in the doi: 10.1158/1078-0432.CCR-09-2574 general population. They might also result from homozy- ©2010 American Association for Cancer Research. gous inactivation of the PTCH1 gene in an early progenitor 442 Clin Cancer Res; 16(2) January 15, 2010 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 12, 2010; DOI: 10.1158/1078-0432.CCR-09-2574 PTCH1 and Nevoid Basal Cell Carcinoma Syndrome which states that both alleles of the tumor suppressor gene Translational Relevance must be inactivated. To answer the question of whether PTCH1 acts as a tu- This study shows the possible mechanisms of mor suppressor gene through a two-hit model in NBCCS PTCH1 inactivation by mutation and/or loss of hetero- patients, we sought to identify the molecular mechanisms zygosity in nevoid basal cell carcinoma syndrome for the two hits inactivating this gene in NBCCS-associated (NBCCS) and its related sporadic tumors. These find- and sporadic KCOTs. A range of PTCH1 alteration profiles, PTCH1 ings imply that will have a potential clinical including genetic mutation, LOH, and promoter hyper- application as a biomarker and a therapeutic target methylation, was investigated to dissect all possible genet- forNBCCS,aswellasitsrelatedsporadictumors. ic and epigenetic mechanisms. The frequent occurrence of PTCH1 mutations in NBCCS suggests that prenatal diagnosis by genetic Materials and Methods counseling is valuable for members in known syn- drome family. As a key player in the Sonic Hedgehog Patients and samples. KCOT samples from 44 unrelated pathway, PTCH1 acts to restrain the activity of SMO Chinese patients (15 NBCCS-related and 29 sporadic and inhibits signal transduction of the pathway. Inac- cases) were obtained from Peking University, Hospital tivation of PTCH1 allows hedgehog ligand-indepen- and School of Stomatology, all of which were previously dent activation of SMO, causing a downstream described for PTCH1 mutations (27 mutations were de- activation of the pathway that may lead to neoplastic tected in 9 of 29 sporadic and 13 of 15 NBCCS-associated growth. Therefore, future identification of inhibitors of KCOTs; Table 1). Diagnosis of NBCCS was established ac- the hedgehog signaling pathway as new drugs will cording to previously described clinical criteria (24). Fresh offer new strategies for the treatment of NBCCS and tissue specimens and corresponding peripheral blood its related sporadic tumors, including keratocystic samples were collected and stored at -80°C for subsequent odontogenic tumors. analysis. As control, two normal gingival samples were ob- tained from healthy volunteers after tooth extraction. The protocol for the experiment was reviewed and approved by the Ethics Committee of Peking University Health Sci- cell of the relevant tissue. Our previous studies (9–12), as ence Center. Informed consent was obtained from all pa- well as others (13–15), have revealed that >85% of tients and volunteers. NBCCS-associated KCOTs and nearly 30% of sporadic Sequencing analysis to determine allelic location of two KCOTs harbored PTCH1 mutations. In addition, loss of coincident mutations. Inthefivetumors(NB9,NB11, heterozygosity (LOH) at chromosome 9q22-31, the region NB19, KC19, and KC21) that were previously found to to which the PTCH1 gene maps, has been observed as a have two concomitant PTCH1 mutations by intragenic frequent event in NBCCS-associated tumors, although dif- mutation screening, cloning sequencing of the reverse ferent estimates of the prevalence of LOH (16-75%) were transcriptase-PCR products containing both sites of the reported (8, 16–18). Besides, research on NBCCS-related mutations was used to determine whether two variants primitive neuroectodermal tumors has shown that PTCH1 were located in the same or different alleles. Total mutations occurred predominantly in tumors with LOH at RNA was extracted from the five tumors by means of 9q22 (17). These data propose a hypothesis that PTCH1 Trizol reagent (Invitrogen). cDNA was synthesized with might be inactivated through a two-hit mechanism in Superscript Ø First-Strand synthesis system (Invitrogen) tumorigenesis. following the standard protocol. Primers designed to Recently, however, more and more reports describe can- clone specific regions encompassing the two mutational didate tumor suppressors that do not conform to the stan- changes were as follows: NB9-F, 5′-CAG CAC TGG AAA dard two-hit model, including cancer-associated genes ACT CGT CA-3′,NB9-R,5′-CTT TGT CGT GGA CCC whose function can be abolished by inactivation of only ATT CT-3′; NB11-F, 5′-CGC CAG AAG ATT GGA GAA one allele (19), and genes inactivated not only by muta- GA-3′, NB11-R, 5′-CCA GGA GTT TGT AGG CAA GG- tion or LOH, but rather by epigenetic hypermethylation 3′;NB19-F,5′-TGG GAT TAA AAG CAG CGA AC-3′, − (20). Analysis of tumors taken from the PTCH1+/ mice NB19-R, 5′-AGC CCC AGG CTC GTA TAG TT-3′; revealed a retained wild-type allele of the gene and the ab- KC19-F, 5′-ACA AAC TTC GAC CCT TTG GA-3′, KC19- sence of a second hit in these animals, indicating that hap- R, 5′-CAG CAT GGT TAG ACA GGC ATA G-3′; KC21-F, loinsufficiency of PTCH1 may be sufficient for tumor 5′-TCG CCT ATG CCT GTC TAA CC-3′, KC21-R, 5′-CTT development (21, 22). In addition, dominant-negative TGT CGT GGA CCC ATT CT-3′.
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