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Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds
J F Flores1, P M Pollock, G J Walker
1University of Southern California, Institute for Genetic Medical, Department of Biochemistry and Molecular Biology, Los Angeles 90033, USA.
Abstract:
Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identified in a proportion of melanoma kindreds. In the case of CDK4, only one specific mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identification of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1beta) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M531 substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous findings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the 'CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.
Insights
Germline mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene are linked to melanoma risk. This study found CDKN2A mutations in 21% of Australian melanoma families, with other cell cycle genes not significantly associated with predisposition.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Germline mutations in CDKN2A and CDK4 are implicated in familial melanoma.
- Previous studies identified CDKN2A mutations in Australian melanoma kindreds.
- The R24C mutation in CDK4 is the only known pathogenic variant associated with melanoma.
Purpose of the Study:
- To expand the screening of melanoma families for germline mutations in cell cycle control genes.
- To investigate the role of CDKN2A, CDK4, CDKN2B, and alternative CDKN2A transcripts in melanoma predisposition.
- To determine if transcriptional silencing of CDKN2A contributes to melanoma risk in families without detectable mutations.
Main Methods:
- Screening of 48 Australian melanoma families for mutations in CDKN2A, CDK4, and CDKN2B.
- Analysis of alternative exon 1 (E1beta) of CDKN2A.
- Evaluation of CDKN2A allele transcription in families with polymorphisms but no mutations.
Main Results:
- Germline CDKN2A mutations were detected in 10/48 (21%) of the melanoma kindreds.
- A novel D108N substitution in CDKN2A was identified, along with previously observed mutations.
- No association was found between melanoma and untranscribed CDKN2A alleles, R24C CDK4 mutations, CDKN2B mutations, or E1beta mutations in 'CDKN2A-negative' families.
Conclusions:
- Germline CDKN2A mutations are a significant cause of inherited melanoma in the studied Australian population.
- Other investigated cell cycle control genes (CDK4, CDKN2B) and alternative CDKN2A transcripts do not appear to play a major role in melanoma predisposition in these families.
- Further research into the genetic underpinnings of melanoma is warranted, focusing on CDKN2A and potentially other uncharacterized pathways.
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