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

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 mechanisms 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 established in tumors carrying two coincident mutations. PTCH1 mRNA expression and promoter methylation 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.

Case Report Multiple nevoid basal cell carcinoma syndrome associated with congenital orbital teratoma, caused by a PTCH1 frameshift mutation

“…We hypothesize that this rare phenotype likely results from the shortened and nonfunctional truncated PTCH1 protein (p.Asn97LysfxX43), which is expressed from the mutated allele (c.290dupA). To date, more than 80% of reported PTCH1 mutations responsible for NBCCS are nonsense, splice site, insertion, deletion, or duplication mutations that lead to expression of nonfunctional truncated proteins (Boutet et al, 2003;Lo Muzio, 2008), some of which have been confirmed experimentally (Fujii et al, 2003;Pastorino et al, 2005;Pan et al, 2010;Suzuki et al, 2012). These mutations spread along the PTCH1 gene with no preferential hotspot and can arise by several mechanisms.…”

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

“…In addition, patients harboring PTCH1 deletions of less than 2.4 Mb in size do not exhibit phenotypes atypical for NBCCS. (17,18) To clarify the mechanism underlying the association between heterozygous PTCH1 mutations/deletions and their associated NBCCS-related phenotypic manifestations, two independent lines of Ptch1-deficient mice have been constructed: Ptch1 +/-(exon 1/2) and Ptch1 neo 67/+ mice. (19,20) Both models were found to be prone to tumor development, skeletal abnormalities, and increased susceptibility to irradiation.…”

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

“…23 Most of the malformations are caused by PTCH1 haploinsufficiency, indicating that the physiological pathway activity is sensitive to relatively small changes in PTC1 levels. 19,24 One of the main roles of 5' untranslated region (5'UTR) of mRNAs is post-transcriptional regulation of gene expression, starting from the initiation of protein translation. [25][26][27] The 5'UTRs can differ in length, nucleotide content, secondary structures, and the presence of different functional elements.…”