Abstract

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. The patched gene codes for a developmental regulator protein implicated in the sonic hedgehog (SHH) signalling pathway which plays an important role in oncogenic transformation. Patched exhibits tumor suppression function and has been shown to be mutated in skin cancers isolated from DNA repair-proficient patients or from xeroderma pigmentosum (XP), a DNA repair-deficient syndrome. We have reviewed and analyzed in detail the different mutation spectra found on the PTCH gene in these various models. The type and distribution of mutations are quite different between germline, sporadic and XP cancers. Among the germline alterations, there is a preponderance (70%) of rearrangements compared to other tumour types analysed where less than 30% of rearrangements is observed. Typical UV-induced mutations of the patched gene are found prominently in XP basal cell carcinomas (BCCs) and in particular, a significantly higher level (63%) of the UV signature tandem mutations is found compared to sporadic BCC (11%). The location of mutations along the PTCH protein delineates several important functional domains implicated in the biology of this transmembrane receptor.