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Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9
M R Gailani1, S J Bale, D J Leffell
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510.
Abstract:
Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.
Insights
Gorlin syndrome, a cancer predisposition disorder, is linked to chromosome 9q31. Mutations in this region
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Gorlin syndrome is an autosomal dominant disorder.
- It predisposes individuals to basal cell carcinomas, ovarian fibromas, and medulloblastomas.
- The syndrome is characterized by widespread developmental defects, distinguishing it from other hereditary cancer disorders.
Purpose of the Study:
- To investigate if Gorlin syndrome is caused by mutations in a tumor suppressor gene.
- To identify the specific chromosomal region associated with the syndrome.
Main Methods:
- Searched for loss of heterozygosity in sporadic and hereditary tumors.
- Performed genetic linkage studies in Gorlin syndrome kindreds.
Main Results:
- Eleven sporadic basal cell carcinomas and three hereditary tumors showed allelic loss of chromosome 9q31.
- All informative kindreds demonstrated tight linkage between the Gorlin syndrome gene and a marker on chromosome 9q31.
- Loss of heterozygosity implies homozygous inactivation of a tumor suppressor gene.
Conclusions:
- The gene responsible for Gorlin syndrome is located on chromosome 9q31 and functions as a tumor suppressor.
- Homozygous inactivation of this gene leads to tumor development.
- Hemizygous germline mutations result in multiple congenital anomalies.
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