Melanoma

Description

Alternative Names

Causes

The role of the sun cannot be overestimated as the most important cause of prematurely aging skin (called photoaging) and skin cancers. Overall, exposure to ultraviolet (referred to as UVA or UVB) radiation emanating from sunlight accounts for about 90% of the symptoms of premature skin aging, and most of these effects occur by age 20:

• Even small amounts of UV radiation trigger process leading to skin wrinkles.
• Long-term repetitive and cumulative exposure to sunlight appears to be responsible for the vast majority of undesirable consequences of aging skin, including basal cell and squamous cell carcinomas.
• Melanoma is more likely to be caused by intense exposure to sunlight in early life.

UVA and UVB Radiation. When sunlight penetrates the top layers of the skin, ultraviolet (referred to as UVA or UVB) radiation bombards the genetic material, the DNA, inside the skin cells and damages it.

• UVB is the primary agent in sunburning and primarily affects the outer skin layers. UVB is most intense at midday when sunlight is brightest.Slightly over 70% of the yearly UVB dose is received during the summer and only 28% is received during the remainder of the year.
• UVA penetrates more deeply and efficiently, however. UVA's intensity also tends to be less variable both during the day and throughout the year than UVB's. For example, only about half of the yearly UVA dose is received during the summer months and the balance is spread over the rest of the year. UVA is also not filtered through window glass (as UVB is).

Damaging Effects of UV Radiation. Both UVA and UVB rays cause damage, including genetic injury, wrinkles, lower immunity against infection, aging skin disorders, and cancer, although the mechanisms are not yet fully clear. The following are some ways in which cancer may develop and some defensive actions that the skin uses to defend itself against DNA damage.

• Oxidation and Antioxidants. The effects of UV radiation are implicated in the production of oxidants, also called free radicals. These are unstable molecules produced by normal chemical processes in the body that, in excess, can damage the body's cells and even alter their genetic material, contributing to the aging process and sometimes to cancer. The large surface area of the skin makes this organ a prime target for oxidants.
• Defective DNA Repair and Protective Enzymes. Some melanomas and other skin cancers are caused by a breakdown in the mechanisms that help repair DNA damage. This can occur from various causes including an inherited condition called xeroderma pigmentosum (XP). A number of enzymes in the skin help protect against this damage. One repair enzyme called T4 endonuclease 5 (T4N5) is, in fact, being investigated in lotions to protect against skin cancers.
• Breakdown of Immune Protection. Specific immune factors protect the skin, including white blood cells called T lymphocytes and specialized skin cells called Langerhans cells. Such immune factors attack developing cancer cells at the very earliest stages. Unfortunately, certain substances in the skin--of note a chemical called urocanic acid--suppress such immune factors when exposed to sunlight, setting the stage for skin cancers.

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 it 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.

Variations in the Melanocortin-1 Receptor Gene. One study found that the greater the number of variations from normal in a gene called the melanocortin-1 receptor gene, the greater the risk for melanoma. The gene plays an important role in determining if a person has red hair, fair skin, and sensitivity to UV radiation. Interestingly, people who had olive and darker skin and who carried one or more variations of the gene had a higher than average risk for melanoma.

Aging

Aging may weaken the bodys ability to fend off impending cancers, including melanomas. As a person ages, they lose specialized immune cells in the skin (Langerhans cells) that are thought to be responsible for eliminating skin cancers at the very earliest stage when only one or two cancer cells are present. The number of these immune cells decreases with age, possibly setting the stage for skin cancers to take root and thrive in later life.