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Germline mutations of the CDKN2 gene in UK melanoma families
1ICRF Cancer Medicine Research Unit, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Abstract:
Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.
Insights
Germline mutations in the CDKN2 gene increase melanoma risk in families. Researchers identified two new CDKN2 mutations linked to melanoma development and analyzed protein binding to CDK4/CDK6.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Germline mutations in CDKN2 (encoding p16) and CDK4 are linked to hereditary melanoma.
- Understanding these genetic predispositions is crucial for identifying at-risk families.
Purpose of the Study:
- To investigate CDKN2 and CDK4 gene mutations in UK families with a predisposition to melanoma.
- To identify novel mutations and assess their functional impact on melanoma development.
Main Methods:
- Sequencing of all CDKN2 exons and analysis of the CDK4 gene in 27 UK melanoma-prone families.
- Co-segregation analysis and in-vitro binding assays to evaluate mutation effects.
Main Results:
- Five distinct germline CDKN2 mutations were identified in six families, including two novel mutations (88delG and Ala118Thr).
- Novel mutations showed co-segregation with melanoma and likely functional effects on the CDKN2 protein.
- Binding assays confirmed the pathogenicity of Met53Ile and suggested functional impact for Ala118Thr; Arg24Pro showed differential binding to CDK4/CDK6.
Conclusions:
- Germline CDKN2 mutations are a significant cause of hereditary melanoma susceptibility in the studied population.
- Novel CDKN2 mutations identified are likely causal, warranting further investigation into their functional mechanisms.
- Mutations in CDK4 appear uncommon as a cause of hereditary melanoma.