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Sporadic medulloblastomas contain PTCH mutations
C Raffel1, R B Jenkins, L Frederick
1Department of Neurosurgery, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. raffel.corey@mayo.edu
Abstract:
Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental 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 without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.
Insights
Mutations in the PTCH gene are implicated in Gorlin's syndrome and basal cell carcinomas. This study found PTCH gene mutations in sporadic medulloblastomas, suggesting its role in a subset of these pediatric brain tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin's syndrome, is an autosomal dominant disorder linked to developmental defects and cancers.
- The PTCH gene is a candidate gene for NBCCS due to frequent mutations in basal cell carcinomas, a common associated cancer.
- Medulloblastoma, a pediatric central nervous system tumor, is also associated with NBCCS, though most cases lack inherited predisposition.
Purpose of the Study:
- To investigate the role of the PTCH gene in sporadic medulloblastomas.
- To examine for loss of heterozygosity (LOH) and mutations in the PTCH gene in non-inherited medulloblastomas.
Main Methods:
- Analysis of 24 sporadic medulloblastomas for LOH at PTCH loci.
- Single-strand conformational polymorphism and sequencing analysis of the remaining PTCH allele in cases with LOH.
Main Results:
- Loss of heterozygosity (LOH) of the PTCH gene was observed in 5 out of 24 (20.8%) sporadic medulloblastomas.
- Mutations in the remaining PTCH allele were identified in three of the five LOH cases.
- All identified mutations (two duplication insertions, one single base deletion) were located in exon 17 of the PTCH gene.
Conclusions:
- PTCH gene inactivation is involved in the pathogenesis of a subset of sporadic medulloblastomas.
- These findings highlight the potential role of PTCH in both inherited and sporadic forms of medulloblastoma.
- Targeting PTCH pathways may offer therapeutic strategies for specific medulloblastoma cases.