Protein complexes consisting of a cyclin-dependent kinase (CDK4 or CDK6) and cyclin D control passage through the G1 checkpoint of the cell cycle by phosphorylating the retinoblastoma (RB) protein1. The ability of these complexes to phosphorylate RB is inhibited by a family of low molecular weight proteins including p16INK4a (refs 2,3), p15iNK4B (ref 4)? and p18 (ref 5) Germline mutations in the p16INK4a gene have been identified in approximately half of families with hereditary melanoma6–12. In this report, we describe an Arg24Cys mutation in CDK4 in two unrelated melanoma families which do not carry germline p16INK4a mutations6. This mutation was detected in 11/11 melanoma patients, 2/17 unaffecteds and 0/5 spouses. The CDK4-Arg24Cys substitution has previously been identified as a somatic mutation in a melanoma that gives rise to a tumour-specific antigen recognized by autologous cytolytic T lymphocytes13. This mutation has a specific effect on the p16INK4a binding domain of CDK4, but has no effect on its ability to bind cyclin D and form a functional kinase13. Therefore, the germline Arg24Cys mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16INK4a. The only previous example of a dominant oncogene transmitted in the human germline is the RET gene that gives rise to MEN2A14,15 and MEN2B16.
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Sherr, C.J. Mammalian G1 cyclins. cell. 73, 1059–1065 (1993).
Serrano, M., Hannon, G.J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 366, 704–707 (1993).
Serrano, M., Gomez-Lahoz, E., DePinho, R., Beach, D. & Bar-Sagi, D. Inhibition of Ras-induced proliferation and cellular transformation by p16INK4. Science. 267, 249–252 (1995).
Hannon, G.J. & Beach, D. pl5INK4B is a potential effector of TGF-b-induced cell cycle arrest. Nature. 371, 257–261 (1994).
Guan, K-L. et al. Growth suppression of p18, a P16INK4/MTS1 and p14iNK4BMrs2_re|ated CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8, 2939–2952 (1994).
Hussussian, C.J. et al. Germline p16 mutations in familial melanoma. Nature Genet. 8, 15–21 (1994).
Kamb, A. et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nature Genet. 8, 22–26 (1994).
MacGeoch, C. et al. Genetic heterogeneity in familial malignant melanoma Hum. Molec. Genet. 3, 2195–2200 (1994).
Gruis, N.A. et al. Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nature Genet. 10, 351–353 (1995).
Ohta, M. et al. Rarity of somatic and germline mutations of the cyclin dependent kinase 4 inhibitor gene, CDK4I, in melanoma. Cancer Res. 54, 5269–5272 (1994).
Liu, L. et al. .Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. Oncogene. 11, 405–412 (1995).
Walker, G.J. et al. .Mutations of the CDKN2/ p16INK4 gene in Australian melanoma kindreds. Hum. Molec. Genet. 4, 1845–1852 (1995).
Wotfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 269, 1281–1284 (1995).
Mulligan, L.M. et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 363, 458–460 (1993).
Donis-Keller, H. et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum. Molec. Genet. 2, 851–856 (1993).
Hofstra, R.M. et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 367, 375–376 (1994).
Goldstein, A.M., Dracopoli, N.C., Engelstein, M., Fraser, M.C., Clark, W.H., & Tucker, M.A. Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 54, 489–496 (1994).
Goldstein, A.M. et al. Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1 p and evidence for genetic heterogeneity. Am. J. hum. Genet. 52, 537–550 (1993).
Ranade, K. et al. Mutations associated with familial melanoma impair p16INK4 function. Nature Genet. 10, 114–116 (1995).
Hanks, S.K. Homology probing: Identification of cDNA clones encoding members of the protein-serine kinase family. Proc. Natl. Acad. Sci. USA. 84, 388–392 (1987).
Demetrick, D.J., Zhang, H. & Beach, D.H. Chromosomal mapping of human CDK2, CDK4 and CDK6 cell cycle kinase genes. Cyfogenef. Cell Genet. 66, 72–74 (1994).
Fountain, J.W., Bale, S.J., Housman, D.E. & Dracopoli, N.C. Genetics of melanoma. Cancer Surv. 9, 645–671 (1990).
Nancarrow, D.J. et al. Confirmation of chromosome 9p linkage in familial melanoma. Am. J. Hum. Genet. 53, 936–942 (1993).
Laird, R.W, Jaenisch, R. DNA methylation and cancer. Hum. Molec. Genet. 3, 1487–1495 (1994).
Otterson, G.A., Kratzke, R.A., Coxon, A., Kirn, Y.W. & Kaye, F.J. Absence of p16iNK4 is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene. 9, 3375–3378 (1994).
Khatib, Z.A. et al. Coamplification of the CDK4 gene with MDM2 and GLI. in human sarcomas. Cancer Res. 53, 5535–5541 (1993).
Ladanyi, M. et al. MDM2 and CDK4 gene amplification in Ewing's sarcoma. J. Pathol. 175, 211–217 (1995).
Schmidt, E.E., Ichimura, K., Reifenberger, G. & Collins, V.R. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 54, 6321–6324 (1994).
He, J. et al. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines. Cancer Res. 54, 5804–5807 (1994).
Separation Technique File No.131: PCR-SSCP Analysis. Pharmacia Biotech, Alameda, Ca. (1995).
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Zuo, L., Weger, J., Yang, Q. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12, 97–99 (1996). https://doi.org/10.1038/ng0196-97
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