Molecular aspects of melanoma
Much of the resistance of melanoma to immunotherapy, radiotherapy and cytotoxic treatment is due to an impressive array of molecular defences that derive ultimately from the essential molecular structure of the melanocyte and its biological requirement for defence against apoptosis. The exploration of melanoma susceptibility genes like CDKN2A (inherited in mutated form in 30-40% of families with multiple melanoma-affected members), CDK4 and MC1R has highlighted a number of key pathways in melanomagenesis. Others have been revealed by a systematic exploration of somatic chromosomal and genetic abnormalities in naevi and melanomas.
Constitutive activating mutations in Nras and BRAF are the most common somatic oncogene mutation in melanoma, indicating the importance of this pathway in the deregulation of melanocyte growth. Downstream targets of this signalling pathway include the cell cycle regulator cyclin D1 and the melanocyte-specific transcription factor, MITF. BRAF mutations are also seen in 60-80% of benign melanocytic naevi. This suggests that the complex molecular machinery of checks and balances in the cell normally protects against the unrestrained growth stimuli propagated through such abnormalities in the Ras/RAF signalling pathway. The CDKN2A product, p16INK4A is induced by activation of the BRAF pathway and under normal circumstances induces cellular senescence. Escape from this senescence is probably fundamental to melanomagenesis.
Melanoma-associated NRas and BRAF mutations do not carry the UV-induced fingerprint, and BRAF mutations appear to be more common in melanomas arising in non-chronically sun-damaged skin and in those with multiple naevi. They are rare in mucosal melanomas and in cutaneous melanoma arising in chronic sun-damaged skin (Curtin, JA et al. N Engl J Med, 353: 2005).
The alternate protein product of the CDKN2A gene, p14ARF binds hdm2 leading to stabilisation of the central apoptosis regulator, p53. Inhibitors of apoptosis, like Bcl-2 and Mcl-1 are frequently over-expressed in established melanomas, accounting in part for the observed resistance of melanoma to cytotoxic attack.