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Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds.
Oncogene 1997; 15(24):2999-3005O

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.

Authors+Show Affiliations

University of Southern California, Institute for Genetic Medical, Department of Biochemistry and Molecular Biology, Los Angeles 90033, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9416844

Citation

Flores, J F., et al. "Analysis of the CDKN2A, CDKN2B and CDK4 Genes in 48 Australian Melanoma Kindreds." Oncogene, vol. 15, no. 24, 1997, pp. 2999-3005.
Flores JF, Pollock PM, Walker GJ, et al. Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. Oncogene. 1997;15(24):2999-3005.
Flores, J. F., Pollock, P. M., Walker, G. J., Glendening, J. M., Lin, A. H., Palmer, J. M., ... Fountain, J. W. (1997). Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. Oncogene, 15(24), pp. 2999-3005.
Flores JF, et al. Analysis of the CDKN2A, CDKN2B and CDK4 Genes in 48 Australian Melanoma Kindreds. Oncogene. 1997 Dec 11;15(24):2999-3005. PubMed PMID: 9416844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. AU - Flores,J F, AU - Pollock,P M, AU - Walker,G J, AU - Glendening,J M, AU - Lin,A H, AU - Palmer,J M, AU - Walters,M K, AU - Hayward,N K, AU - Fountain,J W, PY - 1998/1/7/pubmed PY - 1998/1/7/medline PY - 1998/1/7/entrez SP - 2999 EP - 3005 JF - Oncogene JO - Oncogene VL - 15 IS - 24 N2 - 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/9416844/Analysis_of_the_CDKN2A_CDKN2B_and_CDK4_genes_in_48_Australian_melanoma_kindreds_ L2 - http://dx.doi.org/10.1038/sj.onc.1201470 DB - PRIME DP - Unbound Medicine ER -