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Novel Mutations in the p16/CDKN2A Binding Region of the Cyclin-dependent Kinase-4 Gene¹

Department of Dermatology [H. T., A. J. S.], Division of Hematology/Oncology [H. T., E. B., F. G. H.], Massachusetts General Hospital and Dana-Farber/Partner Cancer Care, Boston, Massachusetts 02114, and National Cancer Institute, Bethesda, Maryland 20892 [C. T.]

Mutations in genes that lie in the retinoblastoma pathway have been implicated in the pathogenesis of many tumor types. Two critical components that determine progression from G₁ to S include p16/CDKN2A and CDK4. Alterations in p16/CDKN2A have been well documented in multiple cancers, including melanoma. However, changes in CDK4 are apparently more rare. Only two alterations, both at codon 24, have been identified in CDK4: an activating arginine-to-cysteine transition and a germ-line arginine-to-histidine substitution in one French kindred. In a survey of 20 neuroblastomas, 17 uncultured metastatic melanomas, 33 uncultured primary uveal melanomas, 8 colon cancer cell lines, and 20 primary colon cancer samples, we found no evidence of mutations in exon 2 of CDK4. From our cell lines derived from metastatic melanomas, we detected two alterations in the functionally critical exon 2 of CDK4: a lysine-to-glutamine transition at codon 22 and the arginine-to-histidine mutation at codon 24. These findings document several novel changes in the p16-binding region of CDK4.

¹ This work was supported by an American Cancer Society Institutional Research Grant and a grant from Aid for Cancer Research in honor of Elaine Klubock (to F. G. H.) and partially supported by NIH Postdoctoral Training Grant 5T32AR07098-23 and the Marion Gardner Jackson Trust (to H. T.).

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Massachusetts General Hospital, Jackson 1021, Fruit Street, Boston, MA 02114.

Received 7/18/97. Accepted 10/29/97.

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