Abstract
The p16 gene is located in chromosome 9p21, a region that is linked to familial melanoma and homozygously deleted in many tumour cell lines. We describe eight p16 germline substitutions (one nonsense, one splice donor site and six missense) in 13/18 familial melanoma kindreds. Six of these mutations were identified in 33/36 melanoma cases in nine families, whereas two were detected in normal controls and are not disease-related. The melanoma-specific mutations were detected in 9p21-linked, but not in 1p36-linked, families, thereby confirming previous reports of genetic heterogeneity. Functional analyses of these mutations will confirm those causally related to the development of familial melanoma.
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References
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).
Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).
Nobori, T., Miura, K., Wu, D.J., Lois, A., Takabayashi, K. & Carson, D.A. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753–756 (1994).
Cairns, P. et al. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265, 415–416 (1994).
Cowan, J., Halaban, R. & Francke, U. Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. J. natn. Cancer Inst. 80, 1159–1164 (1988).
Fountain, J.W. et al. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc. natn. Acad. Sci. U.S.A. 89, 10557–10561 (1992).
Petty, E.M. et al. Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: implications for 9p tumour suppressor gene(s). Am. J. hum. Genet. 53, 96–104 (1993).
Cannon-Albright, L. et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13–p22. Science 258, 1148–1152 (1992).
Goldstein, A.M. et al. Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am. J. hum. Genet. 54, 489–496 (1994).
Nancarrow, D.J. et al. Confirmation of chromosome 9p linkage in familial melanoma. Am. J. hum. Genet. 53, 936–942 (1993).
Greene, M.H. & Fraumeni, J.F. The hereditary variant of malignant melanoma (Grune & Stratton, New York, 1979).
Tucker, M.A. Individuals at high risk of melanoma. Pigment Cell Res. 9, 95–109 (1988).
Tucker, M.A. et al. The risk of melanoma and other cancers in melanomaprone families. J. Invest. Dermatol. Suppl. 100, 350s–355s (1993).
Kwiatkowski, D.J. & Diaz, M.O. Dinucleotide repeat polymorphism at the IFNA locus (9p22). Hum. molec. Genet. 1, 658 (1992).
Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).
Ravnik-Glavac, M., Glavac, D. & Dean, M. Sensitivity of single-strand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene. Hum. molec. Genet. 3, 801–807 (1994).
Bale, S.J. et al. Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p. New Engl. J. Med. 320, 1367–1372 (1989).
Goldstein, A.M. et al. Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity. Am. J. hum. Genet. 52, 537–550 (1993).
Clark, W.H. Jr., Elder, D.E. & Guerry, D. IV. Dysplastic nevi and malignant melanoma. In Pathology of the skin (eds Farmer, E. & Hood, A. ) 684–756 (Appleton and Lange, Norwalk, 1990).
MacKie, R.M., Freudenberger, T. & Aitchison, T.C. Personal risk factor chart for cutaneous melanoma. Lancet 2, 487–490 (1989).
Tucker, M.A. et al. Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families. J. Pediatr. 103, 65–69 (1983).
Fountain, J.W., Hudson, T.J., Engelstein, M., Housman, D.E. & Dracopoli, N.C. Dinucleotide repeat polymorphism at the D9S126 locus (9p22). Hum. molec. Genet. 2, 823 (1993).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans:detection of linkage and estimation of recombination. Am. J. hum. Genet. 37, 482–488 (1985).
Smith, C.A.B. Testing for heterogeneity of recombination fraction values in human genetics. Ann. hum. Genet. 27, 175–182 (1963).
Ott, J. Analysis of human genetic linkage (The Johns Hopkins University Press, Baltimore, 1991).
Ott, J. The HOMOG programs. (Columbia University, New York, 1992).
Shuber, A.P., Skoletsky, J., Stern, R. & Handelin, B.L. Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis. Hum. molec. Genet. 2, 159–163 (1993).
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Hussussian, C., Struewing, J., Goldstein, A. et al. Germline p16 mutations in familial melanoma. Nat Genet 8, 15–21 (1994). https://doi.org/10.1038/ng0994-15
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DOI: https://doi.org/10.1038/ng0994-15
