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Skin Cancer molecular biology and genetics

The molecular stages of melanoma pathogenesis are not fully understood, but a number of key genes and pathways have been implicated in the disease.

The melanocortin receptor gene, MC1R, influences skin pigmentation and polymorphisms in this gene are common. Particular variants have been identified that are linked to an increased risk of melanoma.1,2 There is some evidence that polymorphisms in the oculocutaneous albinism gene, OCA2, may also increase risk.3

Other pathways that may play a role in carcinogenesis include the MAPK and HGF/SF-MET signalling pathways.4 Also, 30-50% of melanoma samples demonstrate loss of heterozygosity at chromosome 10q. Some, but not all, of these samples have mutations in the tumour suppressor gene PTEN, suggesting that additional genes in this region are important. Mutations in the BRAF gene have been observed in up to 60% of patient samples but the role of this gene in melanoma has yet to be elucidated.

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Around 10% of melanoma cases have a strong family history of the disease. Family studies suggest that the disease is often inherited as an autosomal dominant condition with reduced penetrance. A family history doubles the risk of developing the disease. Melanoma is rarely inherited as part of cancer syndromes such as the Li Fraumeni syndrome.

Between 25-40% of inherited cases carry mutations in the CDKN2A locus on chromosome 9p22.2,4 This locus harbours two genes, INK4A (p16) and ARF (p14), which influence the RB and p53 pathways. Mutations in CDK4 (p16) have also been reported but are rare. The Melanoma Genetics Consortium () is coordinating the search for additional susceptibility genes in melanoma families.2 Recently a locus at 1p22 has been reported, although the gene has not yet been identified.5

In the future a better understanding of the molecular stages of melanoma may help to improve detection and ultimately treatment of this disease. As UV radiation is the dominant carcinogen in melanoma, genotype information could also be used for targeting behavioural intervention strategies to those at greatest risk.

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References

1. Palmer, J.S., et al., Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet, 2000. 66(1): p. 176-86.
2. Newton Bishop, J.A. and Bishop, D.T., The genetics of susceptibility to cutaneous melanoma. Drugs Today (Barc), 2005. 41(3): p. 193-203.
3. Jannot, A.S., et al., Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma. Eur J Hum Genet, 2005. 13(8): p. 913-20.
4. Chin, L., The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer, 2003. 3(8): p. 559-70.
5. Gillanders, E., et al., Localization of a novel melanoma susceptibility locus to 1p22. Am J Hum Genet, 2003. 73(2): p. 301-13.

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