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Rarity of Somatic and Germline Mutations of the Cyclin-dependent Kinase 4 Inhibitor Gene, CDK4I, in Melanoma¹

Jefferson Cancer Center [M. O., H. N., M. S., D. R., D. B., M. M., C. M. C., K. H.], and the Ocular Oncology Service, Wills Eye Hospital [A. D. S., J. A. S., C. L. S.], Jefferson Medical College, Philadelphia, Pennsylvania 19107

Evidence from cytogenetics, multipoint linkage analyses of familial melanoma, and loss of heterozygosity studies of familial and sporadic melanomas support localization of a melanoma susceptibility or tumor suppressor gene at chromosomal region 9p21–23. Recently, the inhibitor of cyclin-dependent kinase 4 (CDK4I; also known as 16p^INK4, multiple tumor suppressor 1, or CDKN2 gene) has been mapped to 9p21 and shown to be mutated or deleted in a large fraction of cell lines derived from many tumor types, including melanoma, suggesting that this gene could be a melanoma suppressor gene. In order to test for somatic mutations in the CDK4I gene in tumors, DNAs from 30 surgically resected melanomas of both cutaneous and uveal origins were sequenced. No mutations were detected in the coding region of the CDK4I gene, while mutations or deletions were detected in 60% (9 of 15) of the cultured melanoma cell line DNAs. Among presumptive familial cases, nine of which were members of families with one or two other documented melanoma cases, no germline mutations were detected by sequence analysis. A deletion in the second exon of the CDK4I gene was found in one germline allele of a familial melanoma patient from a family with eight affected first degree relatives. These results not only support the suggestion that the CDK4I gene is a familial malignant melanoma gene, they also suggest the presence of another suppressor gene locus within 9p21 which is the target of loss of heterozygosity in sporadic melanomas.

¹ Supported by NIH Grants CA39860, CA51083, and CA39248 (D. B.).

² To whom requests for reprints should be addressed, at Jefferson Cancer Institute, Room 1006 BLSB, 233 South 10th Street, Philadelphia, PA 19107.

Received 8/12/94. Accepted 9/ 1/94.

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