Evidence that haploinsufficiency of Ptch leads to medulloblastoma in mice

The PTCH gene encodes a putative tumor suppressor protein; germline alterat ions in PTCH have been found in patients with the nevoid basal cell carcino ma syndrome (NBCCS), Medulloblastoma, a brain tumor, develops in about 3% o f NBCCS patients, and mutations in PTCH have also been described in a subse t of sporadic medulloblastomas. The search for the causes of medulloblastom a has been hindered by the lack of an appropriate model system for this tum or type. Recently, a transgenic mouse hemizygous for the Ptch gene was gene rated by homologous recombination. Medulloblastomas were found in about 19% of these mice within the first 25 weeks after birth. The status of the wil d-type PTCH allele in these tumors has not been investigated. For clearer d efinition of the role of PTCH as a tumor suppressor in medulloblastoma, 13 cerebellar tumors from transgenic Ptch (+/-) mice were examined for alterat ions in the remaining Ptch allele. A single mutation was found in one tumor , a C-to-A substitution changing a tyrosine to a stop codon; all other tumo rs exhibited a wild-type sequence. Two tumors with normal Ptch cDNA were ex amined by in situ hybridization. Ptch cDNA was found in tumor cells but not in associated tumor stroma. We also examined the mRNA expression levels fo r the remaining Ptch allele, as well as for Gli1, a gene known to be transc riptionally activated by Ptch inactivation. Blot analysis of RNA from the 1 3 tumors shows that Ptch mRNA of appropriate size is expressed in all tumor s at varying levels. Expression of Gli1 was increased in tumors compared to normal cerebellum. These results suggest that deletion of one copy of Ptch may be sufficient to promote medulloblastoma development in mice. Genes Ch romosomes Cancer 28:77-81, 2000. (C) 2000 Wiley-Liss, Inc.