Sporadic Medulloblastomas Contain PTCH Mutations1

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syn drome, is an autosomal dominant disorder that predisposes to develop mental defects and various forms of cancer. 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. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur with out indication of an inherited predisposition. We have examined 24 spo radic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformatlonal polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOHofPTCHin5of24tumors, andinthreeofthesecasesamutationof the remaining allele was identified. Two ofthe mutations were duplication insertions, and the third consisted ofa single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation ofPTCH function is involved in the development of at least a subset of sporadic medulloblastomas.