Loss of heterozygosity of 9q alleles in both familial and sporadic basal cell carcinomas (BCCs) suggests that the NBCCS gene on 9q is acting as a tumour suppressor gene.
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.
None of the genes rearranged in the BCC-specific t(9;16)(q22;p13) translocation have been identified, but we hypothesize that the translocation represents the cytogenetic corollary of a tumorigenic recombination of PTCH with an as yet unknown gene in 16p13.
The gene for this disorder, NBCCS, maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary basal cell carcinomas suggests that it functions as a tumor suppressor.
The PTCH gene was found to contain somatic mutations also in sporadic basal cell carcinomas and medulloblastomas, tumors seen in NBCCS, consistent with PTCH acting as a tumor suppressor.
Also, several structural rearrangements of chromosome arm 9q were seen, which may be of particular interest against the background that a gene for familial BCC (Gorlin syndrome), the PTCH gene, maps to this region.
In situ hybridization revealed high expression of PTCH2 transcripts in both familial and sporadic basal cell carcinomas in similarity to what has been observed for PTCH1, suggesting a negative regulation of PTCH2 by PTCH1.
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.
Thus far only the point mutations in the P53 gene from squamous cell carcinomas and BCCs, and in PTCH gene from BCC of xeroderma pigmentosum (XP) patients appear to be unambiguously attributable to solar UV radiation.
The finding of mutations in the PTCH gene in both Gorlin's syndrome and sporadic basal cell carcinomas has significantly advanced our understanding of the molecular defects that lead to the formation of these tumours.
An early event in BCC formation, loss of heterozygosity (LOH) at the Patched 1 (Ptch1) locus, can be used as a tool to address whether this tumour is monoclonal.
These results indicate that both HIP and PTC gene expression are specifically involved in the development of BCCs, and that the production of HIP is linked with the expression of the PTC gene but not the SHH gene.
Not only do our data indicate the key role played by p53 and PTCH in the development of BCCs, these findings also suggest that UVB may significantly contribute to BCC tumorigenesis.
In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas.
Mutations in the human homologue of Drosophila Patched1 (PTCH1) have been found in several common tumours including basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma (RMS).