Approximately 5% of KCOTs are associated with nevoid basal cell carcinoma (Gorlin) syndrome and 90% of these show genomic inactivation of the PTCH1 gene encoding Patched 1.
Furthermore, by integrating network interaction construction, we found 37 important dysregulated genes (ING3, VEGFA, TP63, MMP11, NRP1, HIF1A, APC, PTCH1, etc.) that are significantly associated with BCC, as well as a few novel potential miRNAs (miR-203, miR-29b, miR-141, miR-7b, miR-9, miR-200a, miR-7c and miR-132) and TFs (MYB, MYC, STAT3, ARNT, PAX5, CUX1, E2F1 and CEBPA).
Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed.
Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC.
Basal cell carcinoma (BCC) is the most common human cancer, characterized by aberrant activation of the hedgehog (HH) signaling pathway resulting from mutations in the patched 1 (PTCH1) or smoothened (SMO) genes.
Accordingly, metabolic alterations due to a single copy loss of Ptch1 in Ptch1<sup>+/-</sup>/ODC<sup>t</sup>/C57BL/6 heterozygous mice may provide insights about the cancer prone phenotype of BCCs in GS patients, including biomarkers/targets for early intervention.
In patients suspected of having BCNS or patients with multiple basal cell carcinomas (BCCs) with a special distribution on the body and no mutation detected in blood, it is worthwhile to search for a shared PTCH1 mutation in their BCCs as this can detect postzygotic mosaicism.
However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation.
Although most BCCs are sporadic, rare individuals with basal cell nevus syndrome (BCNS) harbor germline defects in PTCH1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs.
Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology and highlights a novel nuclear mechanism of SMO-GLI1 signaling that is unresponsive to SMO inhibitors.<b>Significance:</b> This study describes novel noncanonical Hedgehog signaling, where SMO enters the nucleus to activate GLI1, a mode that is unaffected by SMO inhibitors, thus prompting re-evaluation of current BCC treatment as well as new potential therapies targeting nuclear SMO.<i></i>.
Patched (Ptch) receptors are critical negative regulators of Hedgehog signaling, where Ptch1 loss causes basal cell carcinoma and Ptch1;Ptch2 loss disrupts skin and hair follicle development.Adolphe et al. use single molecule fluorescent in situ hybridization to show quantitatively that Ptch receptors create a Hedgehog signaling gradient that may specify hair follicle development.
Genetic studies revealed mutations of the following genes: CTNNB1, KIT, CDKN2A, TP53, SMAD4, ERBB4, and PTCH1, with some differences between the matrical and BCC components.
Aberrant sonic hedgehog signalling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in basal cell naevus syndrome (BCNS).
Considering the fact that activation of Wnt signalling via down-regulation of APC and SFRP5 due to promoter methylation is observed in BCC of the skin, Wnt signalling activation in oesophageal BSCC might be a secondary effect of the PTCH1-inactivating mutations.
By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC-like tumors.
Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported.
The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant.
Here, we present a father and daughter with a high propensity for the development of basal cell carcinoma who were heterozygous for a non-coding germline mutation in the 5' untranslated region (UTR) of PTCH-1 (insertion of a surplus CGG triplet at the site of a seven times CGG repeat).