MUTATIONS IN THE HUMAN HOMOLOG OF DROSOPHILA PATCHED (PTCH) IN BASAL-CELL CARCINOMAS AND THE GORLIN SYNDROME - DIFFERENT IN-VIVO MECHANISMSOF PTCH INACTIVATION

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autoso mal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinoma. The human homologue of Drosophila patched (PTCH) was recently identified, mapped to the NBCCS locus on chromosome 9q22.3, and found mutated in p atients with NBCCS and also in sporadic basal cell carcinomas. Here we show germ-line PTCH mutations in three families with NBCCS. We demons trate that a germ-line PTCH frameshift deletion in one patient with NB CCS was accompanied by loss of the normal copy of PTCH in a tumor deve loped in the same patient, Another basal cell carcinoma from this pati ent did not shaw the loss of the normal copy of PTCH, instead a missen se mutation in a highly conserved residue was identified in the nondel eted allele, illustrating two different mechanisms of PTCH inactivatio n in different tumors derived from the same NBCCS patient, We also sho w somatic PTCH mutations in 4 basal cell carcinomas identified by anal yzing 18 non-NBCCS patients with sporadic tumors. These data provide f urther support for PTCH as an important turner suppressor gene in the development of the most common human cancer.