Proteomic Analysis ofPTCH1+/− Fibroblast Lysate and Conditioned Culture Media Isolated from the Skin of Healthy Subjects and Nevoid Basal Cell Carcinoma Syndrome Patients

Abstract

Background. The pathogenesis underlying the increased predisposition to the development of basal cell carcinomas (BCCs) in the context of Gorlin-Goltz syndrome is linked to molecular mechanisms that differ from sporadic BCCs. Patients with Gorlin syndrome tend to develop multiple BCCs at an early age and present with tumors of non-sun-exposed skin. The aim of this study was to compare the proteomic profile of cultured fibroblast and fibroblast conditioned culture media of PTCH1+ and nonmutated fibroblasts. Results. Proteomic analysis was performed using Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry in PTCH1+ fibroblast conditioned media isolated from not affected sun-protected skin areas of Gorlin patients and from healthy subjects. 12 protein cluster peaks, >5 kDa, had significant differences in their peak intensities between PTCH1+ and PTCH1− subject groups. We detected a strongly MMP1 overexpression in PTCH1+ fibroblasts obtained from NBCCS patients with respect to healthy donors. Conclusion. Protein profiles in the fibroblast conditioned media revealed statistically significant differences between two different types (missense versus nonsense) of PTCH1 mutations. These differences could be useful as signatures to identify PTCH1 gene carriers at high risk for the development of NBCCS-associated malignancies and to develop novel experimental molecular tailored therapies based on these druggable targets.

Skeletal stigmata as keys to access to the composite and ancient Gorlin–Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons

“…The PTCH1 mutations are responsible for the clinical expression of the disease and can be found in a large amount of patients exhibiting a classic phenotype. Differently from other cancer predisposing syndromes, NBCCS doesn't show the correlations between genotype-phenotype (Ponti et al, 2012b(Ponti et al, , 2013b and its wide phenotypic variation does not appear to be related to the type of PTCH1 mutation, nor to any founder effect. Normally the founder effect is defined as an ancestral mutation, that was introduced in the same population by a common ancient progenitor, and that can be found in different affected families apparently unrelated by any kinship, and living in the same geographic area.…”

“…There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral signs and symptoms. The recognition of the inherited skeletal abnormalities, particularly when uncommon, constitute a critical tool to obtain an early recognition of these syndrome both in the archeological remains and in the current population (Ponti et al, 2013a(Ponti et al, , 2013b. Among the hereditary tumor syndromes associated to unique skeletal findings, Nevoid Basal Cell Carcinoma Syndrome (NBCCS; also known as Gorlin syndrome; OMIM #109400) is an autosomal dominant skin disease with an almost complete penetrance and a high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1 (Lo Muzio, 2008;Lo Muzio et al, 2013).…”

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

“…Activation of the WNT/β-catenin signaling pathway has been increasingly appreciated in CAF biology [99,100] especially in the skin background [101]. The expression level of proteins involved in extracellular matrix remodeling, such as MMP1, MMP3, TNC as well as KGF and stroma cell-derived factor 1 alpha, has been associated with the NBCCS-BCCs aggressive clinical phenotype since patients presenting a high number of large BCCs show a higher level of expression compared to non-aggressive clinical phenotype [102]. By contrast, the difference in the protein profile among distinct genetic groups (missense and nonsense) failed to demonstrated definitive data [103,104].…”

Gene Expression and Proteome Analysis as Sources of Biomarkers in Basal Cell Carcinoma

“…Patients suffering from GS develop multiple BCCs at young ages and tumors are more often localized on non-UV-exposed skin [84]. Genetic anomalies of the PTCH1 gene in GS include nonsense, frameshift, in-frame, splice-site, interstitial, and missense mutations [85].…”