While for most human solid tumors genetic alterations of few distinct genetic regions have been found, studies on basal cell carcinomas (BCC) have shown the prevalence of several abnormalities including alterations of the three ras genes, GAP (GTPase activating protein), p53, PTCH (the human homologue of Drosophila patched) and SMOH (the human homologue of Drosophila smoothened).
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).
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.
Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the United Kingdom.P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-κB signaling pathways and has been documented as highly expressed in several types of human cancer.
Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC.
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.
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.
In this work, we have evaluated resistance mechanisms to MAL-PDT developed by three BCC cell lines (ASZ, BSZ and CSZ), derived from mice on a ptch+/- background and with or without p53 expression, subjected to 10 cycles of PDT (10<sup>th</sup>G).
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.
Our finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapy.
Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.
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.
Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC<sup>3</sup> and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment.
Genital BCCs had a larger size (14.05 vs 8.92 mm, P = 0.014), more common presence of ulcers (61.3% vs 32.0%, P = 0.035), shorter epidermal p53 clone (0.33 vs 1.20 mm, P = 0.007), and high p53 expression levels.
In this study, we examined the immunohistochemical expression of p53 and cyclooxygenase-2 (COX-2) in 51 BCCs, nodular and infiltrative subtypes, with various Clark levels.
It is important to note that emerging therapies for treatment of BCCs in patients with a PTCH1 mutation may not be effective in those with a SUFU mutation.