Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling: possible linkage to WNT

Area of Science:

• Genetics and Molecular Biology
• Oncology
• Developmental Biology

Background:

• Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder.
• It is characterized by a predisposition to various cancers, particularly basal cell carcinomas and medulloblastomas.
• The patched (PTCH) gene is a tumor suppressor gene and a key component of the Sonic Hedgehog (SHH) signaling pathway.

Observation:

• A family with Gorlin syndrome presented with typical features like basal cell tumors and craniofacial/bone malformations.
• Unusually, one family member also developed craniopharyngioma, a rare brain tumor.
• A novel constitutional mutation (1047insAGAA) in the PTCH gene was identified in exon 7, leading to premature protein termination.

Findings:

• Tumor analysis revealed loss of heterozygosity in the PTCH gene region in both basal cell carcinomas and craniopharyngioma.
• High expression of beta-catenin was observed in the craniopharyngioma.
• These findings implicate PTCH haploinsufficiency and aberrant Wnt pathway activation in the pathogenesis of these disorders.

Implications:

• The study suggests the SHH/PTCH/SMO pathway plays a crucial role in the development of Gorlin syndrome-associated tumors.
• Aberrant activation of the Wnt pathway may contribute to craniopharyngioma development in this context.
• Understanding these molecular mechanisms could lead to targeted therapeutic strategies for Gorlin syndrome and related cancers.