Causes

Defective Cell Death (Apoptosis). Apoptosis is the last defense of the immune system. It is a natural process of cell-suicide, which occurs when cells are very severely damaged. Apoptosis in the skin kills off cells harmed by UVA so that they do not turn cancerous. (The peeling after sunburn is the result of these dead skin cells.) In some cases, however, genetic mutations or other factors derail apoptosis. If this occurs, the cells can become immortal and continue to proliferate, resulting in skin cancers.

Genetic Factors

A number of genetic factors are being investigated for their role in melanomas, including inherited genes and genetic defects that are acquired from environmental assaults (particularly sunlight).

Mutations in Genes that Regulate Cell Growth. Noninherited mutations in a number of genes that inhibit tumor growth or other cell-protecting properties may account for cancerous changes in moles and for aggressive melanomas. The following are some examples.

• Important studies have now identified a mutation in the BRAF gene that appears to be the most common event in the process that leads to melanoma. Some researchers have observed mutations in 66% of malignant melanomas. Researchers hope that agents that block this gene may be a viable treatment path.
• P16 is a tumor suppressive gene that may be abnormal in some melanoma cases.
• Genetic mutations that regulate Ku70 and Ku80 proteins may disrupt processes that repair strands of DNA.
• Researchers are also studying mutations in a gene that encodes for a substance called epidermal growth factor (EGF). EGF plays a role in skin cell growth and wound healing, and may account for many sporadic (non-inherited) cases of melanoma.
• Of further interest are mutations in genes that regulate Fas proteins, which are involved in apoptosis, a natural process of cell self-destruction. When apoptosis goes awry in melanoma cells, proliferation can become rampant.

CDKN2A Mutations. Mutations in a genetic regulator called CDKN2A are the most common causes of inherited melanoma (which are still very uncommon). (Mutations in this gene also appear in non-inherited cases of melanoma.) Genetic tests are being developed for CDKN2A, although it is not clear if knowing the results of the test would benefit people carrying the gene.