Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis.

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility. NBCCS is caused by mutations in the human homologue (PTCH) of the Drosophila patched gene, a developmental regulator implicated in signaling of hedgehog and smoothened. 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. Because basal cell carcinomas have been observed to develop in association with benign trichoepitheliomas (TEs) in the same lesions, patients, and families and may share the same cell of origin, we have analyzed PTCH for mutations and expression in TEs. We report frameshift and in-frame somatic deletions in this gene and a consistent overexpression of PTCH mRNA in TEs. These findings provide the first evidence of a gene mutation in TEs and identify a common pathogenic pathway for histopathologically similar but prognostically distinct skin tumors. Moreover, these results support the presence of a gatekeeper mechanism in multistep skin tumorigenesis exerted by the altered PTCH signaling pathway.