Rarity of CDK4 germline mutations in familial melanoma

Author:

Goldstein, A. M.

Chidambaram, A.

Halpern, A.

Holly, E. A.

Guerry, D.

Sagebiel, R.

Elder, D. E.

Tucker, M. A.
Author Address

NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S, Room 7004, 6120 Execut Blvd, MSC 723, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Univ Penn, Sch Med, Pigmented Les Study Grp, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Melanoma Clin, San Francisco, CA USA. Goldstein AM NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S, Room 7004, 6120 Execut Blvd, MSC 723, Bethesda, MD 20892 USA.

Abstract:

To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, Is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 Invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma. (C) 2002 Lippincott Williams Wilkins.

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