Melanoma: Genetics


Melanoma is an aggressive skin cancer. Germ‐line mutations in CDKN2A and CDK4 are found in about 20% of melanoma families. Mutations in a variety of genes have been reported in sporadic melanomas.

Keywords: melanoma; CDKN2A; CDK4; mutation; senescence

Figure 1.

Representative section of human skin. The various epidermal and dermal layers and the position of the melanocytes within the basal layer of the epidermis are indicated.

Figure 2.

Example of a superficial spreading melanoma (a) and a nodular melanoma (b). (Kindly provided by Dr Paul Duray.)

Figure 3.

Alternative transcripts and products encoded by the CDKN2A locus. Alternative splicing occurs, indicated by the dotted lines, to produce two transcripts: exons that splice to encode p16 (light shading) and those that encode p14ARF (dark shading).

Figure 4.

p16 inhibits entry into the cell cycle by inhibiting cyclin D/CDK4. p16 expression is induced during both replicative and premature senescence. For progression from G1 into S phase, retinoblastoma protein (pRb) must be phosphorylated by the cyclin D/CDK4 complex which results in the release of the E2F transcription factors and transactivation of their target genes. p16 inhibits this pathway by inhibiting assembly of cyclin D and CDK4.

Figure 5.

Antagonism of HDM2 by p14ARF results in stabilization of p53. HDM2 functions to inhibit the activity and levels of p53 under normal conditions. p14ARF expression is induced during senescence. p14ARF binds to HDM2 and antagonizes its ability to regulate p53, thereby leading to p53 stabilization and G1/S arrest or apoptosis depending on the cellular context.

Figure 6.

PTEN inhibits the PI3‐kinase/Akt signaling pathway. Signals from extracellular growth factors transduced through receptor tyrosine kinases lead to the recruitment of the phosphoinositide 3 kinase (PI3K) and phosphorylation of the phosphatidylinositol 3,4,5‐triphosphate (PIP3) second messenger PI(4,5)P2 at the D‐3 position. PI(3,4,5)P3 then recruits cytosolic signaling proteins to the membrane, for example Akt (also known as PKB). Subsequent activation of Akt then results in the phosphorylation of a range of downstream targets involved in cell proliferation and apoptosis. PTEN antagonizes this signaling pathway by dephosphorylating PI(3,4,5)P3.

Figure 7.

Ras/Raf/MAPK pathway. BRAF functions downstream of Ras in the MAPK pathway. Signals from extracellular growth factors transduced through receptor tyrosine kinases result in activation of BRAF and the MAPK phosphorylation cascade. This results in activation of several nuclear transcription factors leading to cell proliferation.



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Further Reading

Armstrong BK and English DR (1996) Cutaneous melanoma. In: Schottenfeld D and Fraumeni JFJ (eds.) Cancer Epidemiology and Prevention, pp. 1282–1312. New York, NY: Oxford University Press.

Balch CM, Houghton AN, Sober AJ and Soong S (eds.) (1998) Cutaneous Melanoma St Louis, MO: Quality Medical Publishing.

Box NF, Duffy DL, Chen W, et al. (2001) MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. American Journal of Human Genetics 69: 765–773.

Drayton S and Peters G (2002) Immortalisation and transformation revisited. Current Opinion in Genetics and Development 12: 98–104.

Leslie NR and Downes CP (2002) PTEN: the down side of PI 3‐kinase signalling. Cellular Signalling 14: 285–295

Lundberg AS, Hahn WC, Gupta P and Weinberg RA (2000) Genes involved in senescence and immortalization. Current Opinion in Cell Biology 12: 705–709.

Marks R (2002) The changing incidence and mortality of melanoma in Australia. Recent Results in Cancer Research 160: 113–121.

Ryan KM, Phillips AC and Vousden KH (2001) Regulation and function of the p53 tumor suppressor protein. Current Opinion in Cell Biology 13: 332–337.

Sherr CJ and Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1‐phase progression. Genes and Development 13: 1501–1512.

Sherr CJ and Weber JD (2000) The ARF/p53 pathway. Current Opinion in Genetics and Development 10: 94–99.

Web Links

Cyclin‐dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) (CDKN2A); Locus ID: 1029. LocusLink:

Cyclin‐dependent kinase 4 (CDK4); Locus ID: 1019. LocusLink:

Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R); Locus ID: 4157. LocusLink:

Phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN); Locus ID: 5728. LocusLink:

v‐raf murine sarcoma viral oncogene homolog B1 (BRAF); Locus ID: 673. LocusLink:

Cyclin‐dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) (CDKN2A); MIM number: 600160. OMIM:‐post/Omim/dispmim?600160

Cyclin‐dependent kinase 4 (CDK4); MIM number: 123829. OMIM:‐post/Omim/dispmim?123829

Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R); MIM number: 155555. OMIM:‐post/Omim/dispmim?155555

Phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN); MIM number: 601728. OMIM:‐post/Omim/dispmim?601728

v‐raf murine sarcoma viral oncogene homolog B1 (BRAF); MIM number: 164757. OMIM:‐post/Omim/dispmim?164757

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How to Cite close
Pollock, Pamela M(Jan 2006) Melanoma: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0006064]