Germline mutations of the human patched gene, PTCH, are responsible for the nevoid basal cell carcinoma (NBCC) syndrome or Gorlin's syndrome, characterized by multiple skin cancers, internal cancers and severe developmental abnormalities.
With identification of the Hedgehog receptor PTCH1 as a tumour suppressor gene that underlies the human nevoid basal cell carcinoma syndrome (NBCCS), the Hedgehog signalling pathway was firmly linked to cancer.
This is the first reported case of NBCCS due to a tandem multiexon duplication of PTCH1 representing a novel mechanism leading to the NBCCS phenotype, and highlights the importance of copy number analysis as an adjunct to exon sequencing in identifying infrequent mutational events in PTCH1.
Thus, our data suggest that the non-canonical Hh pathway mediated through ptch1 and cyclin B1 is involved in the pathogenesis of NBCCS-associated KCOTs.
Causative mutations for NBCCS occur in the PTCH1 gene on chromosome 9q22.3-q31, which encodes the principle receptor for the Hedgehog signalling pathway.
Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome.
PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome.
Gorlin syndrome results from heterozygous mutations in the PTCH1 gene for 60% of patients, and we therefore aimed to highlight correlations between intrinsic radiosensitivity and PTCH1 gene expression in fibroblasts from adult patients with Gorlin syndrome.
This new Ptch1 allele broadens the mouse genetic reagents available to study the Hedgehog pathway and provides a valuable means to study the underlying skeletal abnormalities in BCNS.
Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion.
Patched 1 gene mutation has also been identified as the underlying mechanism in most cases of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome).
A total of 8 single-nucleotide variants (SNVs) were detected in PTCH1, PTCH2 and SUFU in all the 5 subjects, however none of them was considered the pathogenic genetic mutation in this NBCCS family.
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.