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Mutation testing in melanoma families: INK4A, CDK4 and INK4D
J A Newton Bishop1, M Harland, D C Bennett
1ICRF Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK.
Abstract:
The INK4A gene which codes for the cyclin-dependent kinase (CDK) inhibitor INK4A or p16 underlies susceptibility to melanoma in some families. Germline mutations in the gene that codes for the target protein of p16, CDK4, underlie susceptibility in very rare families. We report mutation screening of the INK4A and CDK4 genes in 42 UK families. A total of nine families were identified with INK4A mutations and none with CDK4 exon 2 mutations. These mutations were in 8/22 (35%) families with three or more cases of melanoma and 1/20 (5%) families with only two cases. In one of these nine families a novel single base pair substitution was identified, Gly67Arg. In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied. The p19 gene was sequenced in DNA from the 42 UK families and six additional US families. No mutations were identified.
Insights
INK4A gene mutations are linked to melanoma susceptibility in UK families. Screening identified nine families with INK4A mutations, highlighting its role in familial melanoma risk.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The INK4A gene (p16) and CDK4 gene are implicated in familial melanoma susceptibility.
- Germline mutations in INK4A are a known cause of inherited melanoma risk.
- CDK4 mutations are a very rare cause of familial melanoma.
Purpose of the Study:
- To screen INK4A and CDK4 genes for mutations in UK families with a history of melanoma.
- To investigate the p19 INK4D gene as a potential melanoma susceptibility gene.
Main Methods:
- Mutation screening of INK4A and CDK4 genes in 42 UK families.
- Sequencing of the p19 INK4D gene in 42 UK families and 6 additional US families.
Main Results:
- Nine out of 42 families (21%) had INK4A mutations.
- INK4A mutations were found in 35% of families with three or more melanoma cases, versus 5% with two cases.
- No CDK4 exon 2 or p19 INK4D mutations were identified in any families.
- A novel INK4A mutation, Gly67Arg, was identified in one family.
Conclusions:
- INK4A mutations are a significant cause of inherited melanoma susceptibility in the UK.
- CDK4 and p19 INK4D do not appear to be major susceptibility genes for melanoma in the studied families.
- Further research may be needed to identify other melanoma susceptibility genes.