Skip to main content

Advertisement

SpringerLink
Log in

New developments in melanoma genetics

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Research over the last decade has unraveled many details of genetic susceptibility to melanoma. The most recent advances include the characterization of variants outside the coding region of the CDKN2A gene associated with melanoma predisposition. A mutation in the 5′ untranslated region (UTR) of CDKN2A generates a novel upstream initiation codon that abrogates expression of p16, and a common polymorphism in the 3′ UTR is associated with increasing familial risk of melanoma. Other studies have assessed CDKN2A mutation status and non-melanoma cancers, atypical nevi, and the development of multiple primary melanomas, and provided information valuable for screening of individuals who are at risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Soufir N, Avril MF, Chompret A, et al.: Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France: the French Familial Melanoma Study Group. Hum Mol Genet 1998, 7:209–216.

    Article  PubMed  CAS  Google Scholar 

  2. MacKie RM, Andrew N, Lanyon WG, et al.: CDKN2A germline mutations in UK patients with familial melanoma and multiple primary melanomas. J Invest Dermatol 1998, 111:69–272.

    Article  Google Scholar 

  3. Kamb A, Shattuck-Eidens D, Eeles R, et al.: Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994, 8:23–26.

    Article  PubMed  CAS  Google Scholar 

  4. Hussussian CJ, Struewing JP, Goldstein AM, et al.: Germline p16 mutations in familial melanoma. Nat Genet 1994, 8:15–21.

    Article  PubMed  CAS  Google Scholar 

  5. Newton Bishop JA, Harland M, Bennett DC, et al.: Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Br J Cancer 1999, 80:295–300. CDKN2A mutations were found in eight of 22 (35%) British families with at least three melanoma cases but in only one of 20 (5%) twocase families. The closely related CDKN2D gene was analyzed in 42 UK and 6 US families, but no mutations were found. Similarly, no mutations of the CDK4 gene were detected.

    Article  PubMed  CAS  Google Scholar 

  6. Holland EA, Schmid H, Kefford RF, et al.: CDKN2A (P16INK4a) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosom Cancer 1999, 25:339–348. N2A mutations were found in 10 of 66 (15.1%) Australian families with at least three melanoma cases but in only one of 65 (1.5%) two-case families. No mutations of the CDK4 gene were detected in these families

    Article  PubMed  CAS  Google Scholar 

  7. Flores JF, Pollock PM, Walker GJ, et al.: Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. Oncogene 1997, 15:2999–3005.

    Article  PubMed  CAS  Google Scholar 

  8. Ruas M, Peters G: The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1998, 1378:F115-F177.

    PubMed  CAS  Google Scholar 

  9. Goldstein AM, Fraser MC, Struewing JP, et al.: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 1995, 333:970–974.

    Article  PubMed  CAS  Google Scholar 

  10. Borg A, Johannsson U, Johannsson O, et al.: Novel germline p16 mutation in familial malignant melanoma in southern Sweden. Cancer Res 1996, 56:2497–2500.

    PubMed  CAS  Google Scholar 

  11. Ciotti P, Strigini P, Bianchi-Scarra G: Familial melanoma and pancreatic cancer. N Engl J Med 1996, 334:469–470.

    Article  PubMed  CAS  Google Scholar 

  12. Whelan AJ, Bartsch D, Goodfellow PJ: Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 1995, 333:975–977.

    Article  PubMed  CAS  Google Scholar 

  13. Hashemi J, Linder S, Platz A, et al.: Melanoma development in relation to non-functional p16/ink4A protein and dysplastic naevus syndrome in Swedish melanoma kindreds. Melanoma Res 1999, 9:21–30. Occurrence of dysplastic nevi (DN) was analyzed in individuals from five Swedish melanoma kindreds with CDKN2A mutations. A significant association was found between DN and CDKN2A mutation status.

    Article  PubMed  CAS  Google Scholar 

  14. 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 1999, 21:128–132. First report of a disease-causing mutation in CDKN2A outside the p16 coding region. A single nucleotide substitution 34 nucleotides upstream of the wild-type start codon creates a novel initiation codon that is out-of-frame with respect to p16. To date this is the most common CDKN2A mutation in the Canadian population and derives from a common ancestor of British descent.

    Article  PubMed  Google Scholar 

  15. Yarbrough WG, Aprelikova O, Pei H, et al.: Familial tumor syndrome associated with a germline nonfunctional p16INK4a allele. J Natl Cancer Inst 1996, 88:1489–1491.

    Article  PubMed  CAS  Google Scholar 

  16. Platz A, Hansson J, Mansson-Brahme E, et al.: Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. J Natl Cancer Inst 1997, 89:697–702.

    Article  PubMed  CAS  Google Scholar 

  17. Puig S, Ruiz A, Castel T, et al.: Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene. Hum Genet 1997, 101:359–364.

    Article  PubMed  CAS  Google Scholar 

  18. Yakobson EA, Zlotogorski A, Shafir R, et al.: Screening for tumour suppressor p16(CDKN2A) germline mutations in Israeli melanoma families. Clin Chem Lab Med 1998, 36:645–648.

    Article  PubMed  CAS  Google Scholar 

  19. Ghiorzo P, Ciotti P, Mantelli M, et al.: Characterization of Ligurian melanoma families and risk of occurrence of other neoplasia. Int J Cancer 1999, 83:441–448. Non-melanoma cancers were assessed in 14 melanoma families from Liguria, Italy, including seven with the same CDKN2A mutation and seven without mutations. Statistically significant excesses of pancreatic cancer in CDKN2A mutation-positive families and breast cancer in CDKN2A mutation-negative families were reported; however, because the genotypes of many of the individuals were not determined, these conclusions are highly speculative.

    Article  PubMed  CAS  Google Scholar 

  20. Clark WH Jr, Reimer RR, Greene M, et al.: Origin of familial malignant melanomas from heritable melanocytic lesions: the B-K mole syndrome. Arch Dermatol 1978, 114:732–738.

    Article  PubMed  Google Scholar 

  21. Newton Bishop JA: Familial melanoma. Clin Exp Dermatol 1993, 18:5–11. A set of clinical criteria to define the atypical mole syndrome phenotype was proposed.

    Article  PubMed  CAS  Google Scholar 

  22. Wachsmuth RC, Harland M, Newton Bishop JA: The atypical mole syndrome and predisposition to melanoma. New Engl J Med 1998, 339:348–349. Sixty-four individuals from five UK melanoma families with CDKN2A mutations were assessed for the atypical mole syndrome (AMS) phenotype (based on a variable scale). AMS was found to be significantly correlated with CDKN2A mutation carrier status, although a large degree of overlap in phenotype was seen between those with and those without mutations.

    Article  PubMed  CAS  Google Scholar 

  23. Monzon J, Liu L, Brill H, et al.: CDKN2A mutations in multiple primary melanomas. New Engl J Med 1998, 338:879–887. First report of germline CDKN2A mutations in melanoma cases without a family history of the disease, ie, apparently sporadic cases. Notably, these cases had multiple primary melanomas.

    Article  PubMed  CAS  Google Scholar 

  24. Burden AD, Newell J, Andrew N, et al.: Genetic and environmental influences in the development of multiple primary melanoma. Arch Dermatol 1999, 135:261–265. This report is from a Scottish population-based case-control study whose aim is to identify risk factors for the development of multiple primary melanomas (MPM).

    Article  PubMed  CAS  Google Scholar 

  25. Aitken J, Welch J, Duffy D, et al.: CDKN2A variants in a population-based sample of Queensland families with melanoma. J Natl Cancer Inst 1999, 91:446–452. Report from the largest population-based study of melanoma carried out to date. CDKN2A mutations were found only in nine of 87 (10.3%) families deemed at high risk of melanoma based on strength of family history of the disease.

    Article  PubMed  CAS  Google Scholar 

  26. MacLennan R, Green AC, McLeod GR, et al.: Increasing incidence of cutaneous melanoma in Queensland, Australia. J Natl Cancer Inst 1992, 84:1427–1432.

    Article  PubMed  CAS  Google Scholar 

  27. Hayward N: Malignant melanoma. In Inherited Susceptibility to Cancer. Edited by Foulkes WD, Hodgson SV. Cambridge: Cambridge University Press; 1998:279–305.

    Google Scholar 

  28. Hannon GJ, Beach D: p15INK4B is a potential effector of TGF-b-induced cell cycle arrest. Nature 1994, 371:257–261.

    Article  PubMed  CAS  Google Scholar 

  29. Mao L, Merlo A, Bedi G, et al.: A novel p16INK4A transcript. Cancer Res 1995, 55:2995–2997.

    PubMed  CAS  Google Scholar 

  30. Stone S, Jiang P, Dayananth P, et al.: Complex structure and regulation of the P16 (MTS1) locus. Cancer Res 1995, 55:2988–2994.

    PubMed  CAS  Google Scholar 

  31. Stone S, Dayananth P, Jiang P, et al.: Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 1995, 11:987–991.

    PubMed  CAS  Google Scholar 

  32. FitzGerald MG, Harkin DP, Silva-Arrieta S, 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 U S A 1996, 93:8541–8545.

    Article  PubMed  CAS  Google Scholar 

  33. Fargnoli MC, Chimenti S, Keller G, et al.: CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds. J Invest Dermatol 1998, 111:1202–1206.

    Article  PubMed  CAS  Google Scholar 

  34. Liu L, Goldstein AM, Tucker MA, et al.: 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 1997, 19:52–54.

    Article  PubMed  Google Scholar 

  35. van der Velden PA, Sandkuijl LA, Bergman W, et al.: A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families. Genome Res 1999, 9:575–580. This report provides evidence of a modifier locus for melanoma susceptibility mapping to within 15 centimorgans (approximately 15 megabases) proximal to CDKN2A.

    PubMed  Google Scholar 

  36. Parris CN, Harris JD, Griffin DK, et al.: Functional evidence of novel tumor suppressor genes for cutaneous malignant melanoma. Cancer Res 1999, 59:516–520.

    PubMed  CAS  Google Scholar 

  37. Bahuau M, Vidaud D, Jenkins RB, et al.: Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res 1998, 58:2298–2303.

    PubMed  CAS  Google Scholar 

  38. Gao L, Liu L, van Meyel D, et al.: Lack of germ-line mutations of CDK4, p16(INK4A), and p15(INK4B) in families with glioma. Clin Cancer Res 1997, 3:977–981.

    PubMed  CAS  Google Scholar 

  39. Petty EM, Gibson LH, Fountain JW, et al.: Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: implications for 9p tumor-suppressor gene(s). Am J Hum Genet 1993, 53:96–104.

    PubMed  CAS  Google Scholar 

  40. Kamijo T, Bodner S, van de Kamp E, et al.: Tumor spectrum in ARF-deficient mice. Cancer Res 1999, 59:2217–2222.

    PubMed  CAS  Google Scholar 

  41. Zuo L, Weger J, Yang Q, et al.: Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 1996, 12:97–99.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Joint Experimental Oncology Programme of the Queensland Institute of Medical Research, University of Queensland and the Queensland Cancer Fund, PO Royal Brisbane Hospital, 4029, QLD, Australia

    Nicholas Hayward PhD

Authors
  1. Nicholas Hayward PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hayward, N. New developments in melanoma genetics. Curr Oncol Rep 2, 300–306 (2000). https://doi.org/10.1007/s11912-000-0022-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-000-0022-z

Keywords

Search

Navigation