Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma

Nature Genetics volume 21, pages 128–132 (1999)Cite this article

Abstract

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance1,2,3,4,5,6,7,8. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families5,6,7,9. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point10,11,12. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease8,9,13,14,15,16,17,18,19, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers9. We show here that a subset of these kindreds possess a G→T transversion at base –34 of CDKN2A, designated G–34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G–34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The G–34T mutation gives rise to a potential initiation codon.
Figure 2: Cosegregation of the G–34T mutation with melanoma.
Figure 3: Translation initiation from the mutant AUG blocks wild-type protein expression.
Figure 4: Both G–34T and wild-type alleles are transcribed in lymphocytes.
Figure 5: Loss of the wild-type allele in malignant tissue.
Figure 6: Haplotyping of individuals with the G–34T mutation.

Similar content being viewed by others

References

  1. 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. Dermatol. 103, 122S–125S (1994).

    Article  CAS  Google Scholar 

  2. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bale, S.J., Chakravarti, A. & Greene, M.H. Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominance and pleiotropy. Am. J. Hum. Genet. 38, 188–196 ( 1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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  Google Scholar 

  5. Cannon-Albright, L.A. et al. Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM). Cancer Res. 54, 6041–6044 (1994).

    CAS  PubMed  Google Scholar 

  6. Goldstein, A.M., Fraser, M.C., Clark, W.H. Jr & Tucker, M.A. Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi. J. Natl Cancer. Inst. 86, 1385–1390 ( 1994).

    Article  CAS  Google Scholar 

  7. Goldstein, A.M. & Tucker, M.A. Genetic epidemiology of familial melanoma. Dermatol. Clin. 13, 605–612 (1995).

    Article  CAS  Google Scholar 

  8. Hogg, D. et al. Role of the cyclin-dependent kinase inhibitor CDKN2A in familial melanoma. J. Cutan. Med. Surg. 2, 172– 179 (1998).

    Article  CAS  Google Scholar 

  9. Hayward, N.K. The current situation with regard to human melanoma and genetic inferences. Curr. Opin. Oncol. 8, 136– 142 (1996).

    Article  CAS  Google Scholar 

  10. Kamb, A. Cell-cycle regulators and cancer. Trends Genet. 11, 136–140 (1995).

    Article  CAS  Google Scholar 

  11. Sherr, C.J. & Roberts, J.M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149– 1163 (1995).

    Article  CAS  Google Scholar 

  12. Sherr, C.J. Cancer cell cycles. Science 274, 1672– 1677 (1996).

    Article  CAS  Google Scholar 

  13. Hussussian, C.J. et al. Germline p16 mutations in familial melanoma. Nature Genet. 8, 15–21 ( 1994).

    Article  CAS  Google Scholar 

  14. Kamb, A. et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nature Genet. 8, 23–26 (1994).

    Article  CAS  Google Scholar 

  15. Gruis, N.A., Sandkuijl, L.A., van der Velden, P.A., Bergman, W. & Frants, R.R. CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. Melanoma Res. 5, 169– 177 (1995).

    Article  CAS  Google Scholar 

  16. Holland, E.A. et al. Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. Oncogene 11, 2289– 2294 (1995).

    CAS  PubMed  Google Scholar 

  17. Walker, G.J. et al. Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum. Mol. Genet. 4, 1845– 1852 (1995).

    Article  CAS  Google Scholar 

  18. Liu, L. et al. Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. Oncogene 11, 405 –412 (1995).

    CAS  PubMed  Google Scholar 

  19. FitzGerald, M.G. et al. 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 (1996).

    Article  CAS  Google Scholar 

  20. Monzon, J. et al. CDKN2A mutations in multiple primary melanomas. N. Engl. J. Med. 338, 879–887 (1998).

    Article  CAS  Google Scholar 

  21. Bergenhem, N.C., Venta, P.J., Hopkins, P.J., Kim, H.J. & Tashian, R.E. Mutation creates an open reading frame within the 5´ untranslated region of macaque erythrocyte carbonic anhydrase (CA) I mRNA that suppresses CA I expression and supports the scanning model for translation. Proc. Natl Acad. Sci. USA 89 , 8798–8802 (1992).

    Article  CAS  Google Scholar 

  22. Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genet. 19, 155–157 ( 1998).

    Article  CAS  Google Scholar 

  23. Pollock, P.M. et al. Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families: evidence for common founders and independent mutations. Hum. Mutat. 11, 424–431 (1998).

    Article  CAS  Google Scholar 

  24. MacGeoch, C. et al. Genetic heterogeneity in familial malignant melanoma. Hum. Mol. Genet. 3, 2195–2200 (1994).

    Article  CAS  Google Scholar 

  25. Borg, A. et al. Novel germline p16 mutation in familial malignant melanoma in southern Sweden. Cancer Res. 56, 2497– 2500 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Sidransky and P. Cairns for advice and aliquots of 9p21 markers; J. Kennedy for samples of normal DNA; L. From and M. McKenzie for identification of melanoma-prone families; D. Bailey for assistance with analysis of the liver biopsy specimen; and M. Shennan for assistance in contacting family members. We also thank the patients and their family members who participated in this study. This work was supported by a Terry Fox grant from the National Cancer Institute of Canada (NCIC) to D.H. D.D. is a recipient of a postgraduate scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC).

Author information

Authors and Affiliations

  1. Department of Clinical Science, University of Toronto, Toronto, Ontario, Canada

    Ling Liu, Luzhang Gao, Jose Monzon, Norman Lassam & David Hogg

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    David Dilworth, Norman Lassam & David Hogg

  3. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Norman Lassam & David Hogg

  4. Department of Genetics, North York General Hospital, Ontario, Canada

    Ann Summers

Authors
  1. Ling Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Dilworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luzhang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jose Monzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann Summers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norman Lassam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Hogg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Hogg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, L., Dilworth, D., Gao, L. et al. Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet 21, 128–132 (1999). https://doi.org/10.1038/5082

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/5082

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing