Mutations in the gene coding for the transmembrane receptor protein PTCH, or PTCH1, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.
In the resting state, the transmembrane receptor protein PTCH acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction. Stoichiometric binding of the hedgehog ligand to PTCH releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[50,51] Thus, the balance of PTCH (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.
Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[52,53] Further investigation identified a mutation in PTCH that localized to the area of allelic loss. Up to 30% of sporadic BCCs demonstrate PTCH mutations. In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH mutations, predominantly truncation in type.
Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[57,58]PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension. While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[57,60]
Syndromes Associated with a Predisposition to Basal Cell Cancer
Basal cell nevus syndrome
BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals. The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[56,62] The clinical features of BCNS differ more among families than within families.