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Genes, sunlight and the origins of cutaneous melanoma

Whiteman, D.

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doi: 10.1097/01.cmr.0000382745.30721.a2
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Cutaneous melanomas arise through the action of sunlight on the skin of genetically susceptible individuals. Understanding the precise mechanisms through which sunlight causes melanoma is the aim of much current research. During the past decade, the scale of genetic research has increased rapidly across two domains: constitutional genotyping to identify genes which confer melanoma susceptibility, and genotyping of cancer cells to identify somatic mutations likely to reflect the causal origins of melanoma.

At the level of constitutional genotyping, genome-wide scans have largely confirmed the associations of a clutch of promising candidate genes for melanoma susceptibility in the general population. Genes currently accepted as being positively associated with melanoma at high-frequency (i.e. not familial melanoma genes) include MC1R, ASIP, MTAP, OCA, and TYR1. Most of these genes had been linked previously with phenotypic traits that confer increased risks of melanoma including high naevus counts, red hair and freckling. At the level of somatic mutations, much gene discovery still lies ahead. Two oncogenes (BRAF, NRAS) and three tumour-suppressor genes (TP53, CDKN2A, PTEN) have been identified repeatedly as being mutated in melanoma, albeit at different frequencies, and there is broad consensus that mutations in these genes are causal for melanoma. Consistent with the ‘divergent pathway hypothesis’ for melanoma, there is accumulating evidence that the pattern of somatic mutations observed in melanomas reflects the causal origins of the tumours. For example, BRAF-mutant melanomas are more likely to arise in people with high naevus counts, or exposed to high-levels of sunlight in early life, and to have melanomas histologically associated with naevus remnants than BRAF-wildtype melanomas. New causal genes for melanoma will be discovered using high-throughput sequencing technologies. To date, only one melanoma genome has been sequenced in entirety, yielding new insights into the distributions of UV-specific mutation patterns for melanoma.

The new genotyping and sequencing technologies thus offer considerable potential for understanding the interplay of genes and sunlight for melanoma, however progress will be maximised if investigators keep abreast of current findings and incorporate tests of new hypotheses into their study designs. For example, in constitutional genotyping studies, stratification by the anatomical site of melanoma, and by naevus count, are likely to reveal associations with different groups of susceptibility genes. Similarly, the interpretation of somatic mutation patterns in melanoma will be most meaningful when tumours are analysed according to anatomic site, histology and host phenotype.

Finally while genetics has assumed a dominant position in recent melanoma research, it must not be overlooked that much pigment cell biology remains to be understood. In particular, little is known about the mechanisms underlying the proliferative responses of melanocytes to sunlight, yet this phenomenon is likely to yield valuable insights for melanoma. The challenge for future research is to integrate the developments across all disciplines into a coherent causal model for melanoma.

© 2010 Lippincott Williams & Wilkins, Inc.