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While there are many known risk factors for melanoma, it’s not always exactly clear how they might cause cancer.

For example, while most moles never turn into a melanoma, some do. Researchers have found some gene changes inside mole cells that may cause them to become melanoma cells. But it’s still not known exactly why some moles become cancerous while most don’t.

Gene changes that might lead to melanoma

DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. We usually look like our parents because they are the source of our DNA. But our genes affect more than just how we look.

Some genes control when our cells grow and divide into new cells, repair mistakes in DNA, or cause cells to die when they’re supposed to. If these genes aren’t working properly, it can lead to cells growing out of control. For example:

• Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. These genes can result in cells growing out of control.
• Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. Changes that turn off these genes can result in cells growing out of control.
• Some genes normally help repair mistakes in a cell’s DNA. Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control.

Mutations or other changes in any of these types of genes might lead to cells growing out of control. Changes in several different genes are usually needed for a cell to become a cancer cell. To learn more, see Oncogenes, Tumor Suppressor Genes, and DNA Repair Genes.

Acquired gene mutations

Most often, gene changes related to melanoma are acquired during a person’s lifetime and are not passed on to a person’s children (inherited). Sometimes these acquired mutations seem to happen randomly within a cell, without having a clear cause. At other times, they likely happen as the result of exposure to an outside cause.

For example, ultraviolet (UV) rays are a major cause of melanoma. Most UV rays come from sunlight, but some can come from man-made sources such as tanning beds. UV rays can damage the DNA in skin cells. Sometimes this affects certain genes that control how the cells grow and divide. If these genes no longer work properly, the affected cells may become cancer cells.

In many cases a melanoma might not appear until many years after the DNA damage from UV rays has been done. Children and young adults often get a lot of intense sun exposure that might not result in cancer until many years or even decades later.

The most common change in melanoma cells is a mutation in the BRAF oncogene, which is found in about half of all melanomas. Other genes that can be affected in melanoma include NRAS, CDKN2A, and NF1. (Usually only one of these genes is affected.)

Melanomas that start on the palms of the hands, soles of the feet, or under the nails (known as acral lentiginous melanomas), or on internal surfaces such as the mouth and vagina (mucosal melanomas), often have different gene changes than those in melanomas that develop in sun-exposed areas, such as changes in the C-KIT (or just KIT) gene.

Inherited gene mutations

Less often, people inherit gene changes from a parent that clearly raise their risk of melanoma.

Familial (inherited) melanomas most often have changes in tumor suppressor genes, such as CDKN2A (also known as p16), CDK4, or BAP1, that prevent these genes from doing their normal job of controlling cell growth. This could eventually lead to cancer.

For some people who have a strong family history of melanoma or who have had several melanomas (or melanomas that started at an early age), doctors might advise genetic counseling and testing to see if they have a mutation in one of these genes (or possible other genes) that increases their risk.

Some people, such as those with xeroderma pigmentosum (XP), inherit a change in one of the XP (ERCC) genes, which normally help to repair damaged DNA inside the cell. Changes in one of these genes can lead to skin cells that have trouble repairing DNA damaged by UV rays, so these people are more likely to develop melanoma, especially on sun-exposed parts of the body.

Gene mutations can sometimes affect treatment

Some of the gene changes found in melanoma cells have proven to be good targets for drugs to help treat this disease. For example, drugs that specifically target cells with changes in the BRAF gene or the KIT gene are now used to treat advanced melanomas with these changes (see Targeted Therapy for Melanoma Skin Cancer).