Abstract
The INK4A gene which codes for the cyclin-dependent kinase (CDK) inhibitor INK4A or p16 underlies susceptibility to melanoma in some families. Germline mutations in the gene that codes for the target protein of p16, CDK4, underlie susceptibility in very rare families. We report mutation screening of the INK4A and CDK4 genes in 42 UK families. A total of nine families were identified with INK4A mutations and none with CDK4 exon 2 mutations. These mutations were in 8/22 (35%) families with three or more cases of melanoma and 1/20 (5%) families with only two cases. In one of these nine families a novel single base pair substitution was identified, Gly67Arg. In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied. The p19 gene was sequenced in DNA from the 42 UK families and six additional US families. No mutations were identified.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Bale, S. J., Dracopoli, N. C., Tucker, M. A., Clark, W. H. Jr, Fraser, M. C., Stanger, B. Z., Green, P., Donis-Keller, H., Housman, D. E. & Greene, M. H. (1989) Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p. N Engl J Med 320: 1367–1372.
Bergman, W., Watson, P., de Jong, J., Lynch, H. T. & Fusaro, R. M. (1990) Systemic cancer and the FAMMM syndrome. Br J Cancer 61: 932–936.
Bressac-de-Paillerets, B., Soufir, N., Chompret, A., Bombled, J., Demenais, F., Spatz, A. & Avril, M. (1997) Germ-line mutations in p16 and CDK4 genes in 36 melanoma families. Melanoma Res 7: S132
Cannon-Albright, L., Goldgar, D., Meyer, L., Lewis, C., Anderson, D., Fountain, J., Hegi, M., Wiseman, R., Petty, E., Bale, A., Olopade, O., Diaz, M., Kwiatkowski, D., Piepkorn, M., Zone, J. & Skolnick, M. (1992) Assignment of a locus for familial melanoma MLM, to chromosome 9p13–22. Science 258: 1148–1152.
Clark, W., Reimer, R., Greene, M., Asnworth, A. & Masrangelo, M. (1978) Origin of familial malignant melanoma from hereditable melanocytic lesions: the BK mole syndrome. Arch Dermatol 114: 732
Coleman, K., Wautlet, B., Morrissey, D., Mulheron, J., Sedman, S., Brinkley, P., Price, S. & Webster, K. (1997) Identification of CDK4 sequences involved in cyclin D1 and p16 binding. J Biol Chem 272: 18869–18874.
Dracopoli, N. & Fountain, J. (1996) CDKN2 mutations in melanoma. Cancer Surv 26: 115–132.
Fitzgerald, M., Harkin, D., Silva-Arrieta, S., MacDonald, D., Lucchina, L., Unsal, H., O’Neill, E., Koh, J., Finkelstein, D., Isselbacher, K., Sober, A. & Haber, D. (1996) Prevalence of germ-line mutations in p16, p19ARF and CDK4 in familial melanoma: analysis of a clinic based population. Proc Natl Acad Sci USA 93: 8541–8545.
Gemma, A., Takenoshita, S., Hagiwara, K., Okamoto, A., Spillare, E., McMemamin, M., Hussain, S., Forrester, K., Zariwala, M., Xiong, Y. & Harris, C. (1996) Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4B, p16INK4A, p18 and p19 in human cancer cell lines. Intl J Cancer 68: 605–611.
Goldstein, A. M. & Tucker, M. A. (1997) Screening for CDKN2A mutations in hereditary melanoma. J Natl Cancer Inst 89: 676–678.
Goldstein, A. M., Dracopoli, N. C., Ho, E. C., Fraser, M. C., Kearns, K. S., Bale, S. J., McBride, O. W., Clark, W. H. Jr & Tucker, M. A. (1993) 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.
Goldstein, A. M., Dracopoli, N. C., Engelstein, M., Fraser, M. C., Clark, W. H. Jr & Tucker, M. A. (1994) Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am J Hum Genet 54: 489–496.
Gruis, N. A., Bergman, W. & Frants, R. R. (1990) Locus for susceptibility to melanoma on chromosome 1p. N Engl J Med 322: 853–854.
Guan, K., Jenkins, C., Li, Y., Okeefe, C., Noh, S., Wu, X., Zariwala, M., Matera, A. & Xiong, Y. (1996) Isolation and characterisation of p19(INK4D), a p16-related inhibitor specific to CDK6 and CDK4. Mol Biol Cell 7: 57–70.
Harland, M. H., Meloni, R., Gruis, N., Pinney, E., Brookes, S., Spurr, N. K., Frischauf, A-M, Bataille, V., Peters, G., Cuzick, J., Selby, P., Bishop, D. T. & Newton Bishop, J. (1997) Germline mutations of the CDKN2 gene in UK melanoma families. Hum Mol Genet 6: 2061–2067.
Hirama, T. & Koeffler, H. (1995) Role of the cyclin-dependent inhibitors in the development of cancer. Blood 86: 841–854.
Hussussian, C. J., Struewing, J. P., Goldstein, A. M., Higgins, P., Ally, D. S., Sheahan, M. D., Clark, W. H. Jr, Tucker, M. A. & Dracopoli, N. C. (1994) Germline p16 mutations in familial melanoma. Nat Genet 8: 15–21.
Kamb, A., Shattuck-Eidens, D., Eeles, R., Liu, Q., Gruis, N. A., Ding, W., Hussey, C., Tran, T., Miki, Y., Weaver-Feldhaus, J., McClure, M., Aitken, J. F., Anderson, D. E., Bergman, W., Frants, R., Goldgar, D. E., Green, A., MacLennan, R., Martin, N. G., Meyer, L. J., Youl, P., Zone, J. J., Skolnick, M. H. & Cannon-Albright, L. A. (1994) Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8: 22–26.
Liu, L., Goldstein, A. M., Tucker, M. A., Brill, H., Gruis, N. A., Hogg, D. & Lassam, N. J. (1997) Affected members of melanoma-prone families with linkage to 9p21 but lacking mutations in CDKN2A do not harbor mutations in the coding regions of either CDKN2B or p19ARF. Genes Chromosomes Cancer 19: 52–54.
Lynch, H. T. & Fusaro, R. M. (1991) Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome. Pancreas 6: 127–131.
MacGeoch, C., Newton Bishop, J., Bataille, V., Bishop, D., Frischauf, A., Meloni, R., Cuzick, J., Pinney, E. & Spurr, N. (1994) Genetic heterogeneity in familial malignant melanoma. Hum Mol Genet 3: 2195–2200.
Mann, G., Holland, T., Grulet, O-C, Rizos, H. & Kefford, R. (1997) Mutation and linkage analysis of CDKN2A and CDK4 in 119 Australian melanoma kindreds. Am J Hum Genet 61: A73
Miller, C., Yeon, C., Aslo, A., Mendoza, S., Aytac, U. & Koeffler, H. (1997a) The p19INK4D cyclin dependent kinase inhibitor gene is altered in osteosarcoma. Oncogene 15: 231–235.
Nancarrow, D. J., Palmer, J. M., Walters, M. K., Kerr, B. M., Hafner, G. J., Garske, L., McLeod, G. R. & Hayward, N. K. (1992) Exclusion of the familial melanoma locus (MLM) from the PND/D1S47 and MYCL1 regions of chromosome arm 1p in 7 Australian pedigrees. Genomics 12: 18–25.
Nancarrow, D., Mann, G., Holland, E., Walker, G., Beaton, S., Walters, M., Luxford, C., Palmer, J., Donald, J., Weber, J., Fountain, J., Kefford, R. & Hayward, N. (1993) Confirmation of chromosome 9p linkage in familial melanoma. Am J Hum Genet 53: 936–942.
Nelson, M., Thompson, F., Emerson, J., Aickin, M., Adair, L., Trent, J., Leong, S. & Taetle, R. (1996) Clinical implications of cytogenetic abnormalities in melanoma. Surg Clin N Am 76: 1257–1271.
Newton, J. (1994) Genetics of melanoma. Br Med Bull 50: 677–687.
Parmiter, A., Balaban, G., Herlyn, M., Clark, W. & Nowell, P. (1986) A t(1;19) chromosome translocation in three cases of human malignant melanoma. Cancer Res 46: 1526–1529.
Platz, A., Hansson, J., Mansson-Brahme, E., Lagerlof, B., Linder, S. & Lundqvist, E. (1997) Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. J Nat Cancer Inst 89: 697–702.
Ranada, K., Hussussian, C., Sikorski, R., Varmus, H., Goldstein, A., Tucker, M., Serrano, M., Hannon, G., Beach, D. & Dracopoli, N. (1995) Mutations associated with familial melanoma impair p16 INK4 function. Nat Genet 10: 114–116.
Sherr, C. (1996) Cancer cell cycles. Science 274: 1672–1677.
Sherr, C. & Roberts, J. (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9: 1149–1163.
Shiohara, M., Spirin, K., Said, J. W., Gombart, A. F., Nakamaki, T., Takeuchi, S., Hatta, Y., Morosetti, R., Tasaka, T., Seriu, T., Bartram, C., Miller, C. W., Tomonaga, M. & Koeffler, H. P. (1996) Alterations of the cyclin-dependent kinase inhibitor p19INK4D is rare in hematopoietic malignancies. Leukaemia 10: 1897–1900.
Walker, G. J., Nancarrow, D. J., Walters, M. K., Palmer, J. M., Weber, J. L. & Hayward, N. K. (1994) Linkage analysis in familial melanoma kindreds to markers on chromosome 6p. Intl J Cancer 59: 771–775.
Walker, G., Hussussian, C., Flores, J., Glendening, J., Haluska, F., Dracopoli, N., Hayward, N. & Fountain, J. (1995) Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet 4: 1845–1852.
Yang, R., Serrano, M., Slater, J., Leung, E. & Koeffler, H. P. (1996) Analysis of p16INK4a and its interaction with CDK4. Biochem Biophys Res Commun 218: 254–259.
Zindy, F., Quelle, D., Roussel, M. & Sherr, C. (1997) Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and ageing. Oncogene 15: 203–211.
Zuo, L., Weger, J., Yang, Q., Goldstein, A., Tucker, M., Walker, G., Hayward, N. & Dracopoli, N. (1996) Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12: 97–99.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Bishop, J., Harland, M., Bennett, D. et al. Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Br J Cancer 80, 295–300 (1999). https://doi.org/10.1038/sj.bjc.6690354
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.bjc.6690354
Keywords
This article is cited by
-
Genome-wide association study identifies three loci associated with melanoma risk
Nature Genetics (2009)
-
A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions
European Journal of Human Genetics (2007)
-
Induction of p19INK4d in response to ultraviolet light improves DNA repair and confers resistance to apoptosis in neuroblastoma cells
Oncogene (2005)
-
New developments in melanoma genetics
Current Oncology Reports (2000)
