Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds (original) (raw)

Nature Genetics volume 10, pages 351–353 (1995)Cite this article

Abstract

The p16 gene (CDKN2) which is localized on chromosome 9p21, is deleted in a significant number of sporadic cancers1–3. Moreover, germline mutations identified in some melanoma-prone kindreds4,5 last year suggested that CDKN2 is identical to the 9p21 −linked melanoma susceptibility gene (MLM)6; however, failure to identify p16 mutations in all melanoma kindreds putatively linked to 9p21 left some doubts. We have analysed CDKN2 coding sequences in 15 Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome pedigrees, and identified a 19 basepair (bp) germline deletion in 13 of them. All 13 families originate from an endogamous population. The deletion causes a reading frame shift, predicted to result in a severely truncated p16 protein. Interestingly, two family members are homozygous for the deletion, one of whom shows no obvious signs of disease. This surprising finding demonstrates that homozygotes for this CDKN2 mutation are viable, and suggests the presence of a genetic mechanism that can compensate for the functional loss of p16. Our results also greatly strengthen the notion that p16 is indeed MLM.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).
    Article CAS PubMed Google Scholar
  2. Nobori, T. et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753–756 (1994).
    Article CAS PubMed Google Scholar
  3. 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).
    Article CAS PubMed Google Scholar
  4. 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).
    Article CAS Google Scholar
  5. Hussussian, C.J. et al. Germline p16 mutations in familial melanoma. Nature Genet. 8, 15–21 (1994).
    Article CAS PubMed Google Scholar
  6. Cannon-Albright, L.A. et al. Assignment of a locus for familial melanoma MLM, to chromosome 9p13-p22. Science 258, 1148–1152 (1992).
    Article CAS PubMed Google Scholar
  7. Gruis, N.A. et al. Linkage analysis in Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome families. Effect of naevus count. Melanoma Res. 3, 271–277 (1993).
    CAS PubMed Google Scholar
  8. Bergman, W., Gruis, N.A., Sandkuijl, L.A. & Frants, R.R. Genetics of seven Dutch familial atypical multiple mole-melanoma syndrome families: A review of linkage results including chromosomes 1 and 9. J. Invest. Dermat. 103, 122S–125S (1994).
    Article CAS Google Scholar
  9. Hannon, G.J. & Beach, D. p15INK4B is a potential effector of TGF- β-induced cell cycle arrest. Nature 371, 257–261 (1994).
    Article CAS PubMed Google Scholar
  10. Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).
    Article CAS PubMed Google Scholar
  11. Sah, V.P., Attardi, L.D., Mulligan, G.J., Williams, B.C., Bronson, R.T. & Jacks, T. A subset of _p53_-deficient embryos exhibit exencephaly. Nature Genet. 10, 175–180 (1995).
    Article CAS PubMed Google Scholar
  12. Lee, E.Y.-H.P. et al. Mice deficient for Rb are non viable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–295 (1992).
    Article CAS PubMed Google Scholar
  13. Guan, K.-L. et al. Growth suppression by p18, a p16INK4/MTS1 and p14INK4B/MTS2- related CDK6 inhibitor, correlates with the wild-type pRb function. Genes Dev. 8, 2939–2952 (1994).
    Article CAS PubMed Google Scholar
  14. Bergman, W., Gruis, N.A. & Frants, R.R. The Dutch FAMMM family material: Clinical and genetic data. Cytogenet. cell. Genet. 59, 161–164 (1992).
    Article CAS PubMed Google Scholar
  15. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Acids Res. 16, 1215 (1988).
    Article CAS PubMed PubMed Central Google Scholar
  16. 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).
    Article CAS PubMed Google Scholar
  17. Maniatis, T., Fritsch, E.F. & Sambrook, J. in Molecular Cloning: A Laboratory Manual 2nd edn (Cold Spring Habor Laboratory Press, Cold Spring Habor, 1989).
    Google Scholar

Download references

Author information

Authors and Affiliations

  1. MGC-Department of Human Genetics, Leiden University, The Netherlands
    Nelleke A. Gruis, Pieter A. van der Velden, Lodewijk A. Sandkuijl, Duncan E. Prins & Rune R. Frants
  2. Department of Dermatology, University Hospital Leiden, The Netherlands
    Nelleke A. Gruis, Duncan E. Prins & Wilma Bergman
  3. Myriad Genetics Inc., Salt Lake City, Utah, USA
    Jane Weaver-Feldhaus & Alexander Kamb

Authors

  1. Nelleke A. Gruis
  2. Pieter A. van der Velden
  3. Lodewijk A. Sandkuijl
  4. Duncan E. Prins
  5. Jane Weaver-Feldhaus
  6. Alexander Kamb
  7. Wilma Bergman
  8. Rune R. Frants

Rights and permissions

About this article

Cite this article

Gruis, N., van der Velden, P., Sandkuijl, L. et al. Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds.Nat Genet 10, 351–353 (1995). https://doi.org/10.1038/ng0795-351

Download citation

This article is cited by