Abstract

Skin carcinogenesis has a multistage model where reactive oxygen species, induced by solar radiation, are associated with initiation, promotion and progression. It is appreciated that ultraviolet light directly induces DNA damage in the form of photoproducts, but this sort of mutation is not commonly seen in the driver genes involved in melanoma, such as BRAF. Also, melanoma can occur in non-sun exposed sites. These paradoxes are better explained if it is seen that melanoma is a tumour of oxidative stress as well as direct UV-induced DNA damage. Melanocytes endure exposure to UVR over a lifetime and intermediaries in melanin production can be cytotoxic, so the melanocyte is well served by protective cellular mechanisms. Bulky DNA mutations caused by UV-induced mutations are repaired by nucleotide excision repair. This needs to be immediate and serviced by multiple pathways to maintain genomic stability. As well as the direct influence of UVR causing transition type mutations at dipyrimidine sites, inflammation, immunological responses and oxidative modification of DNA and proteins play a role, such as G:C to T:A transversions, induced by the presence of 8-oxoguanine during DNA replication. Oxidative stress induces genomic instability through activation of proto-oncogenes, such as c-fos, c-Jun and c-myc, and modification of transcriptional and repair processes.