What Causes Melanoma Skin Cancer?

Many risk factors for melanoma have been found, but it’s not always clear exactly 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.

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 DNA affects more than just how we look.

Some genes control when our cells grow, divide into new cells, and die:

• Genes that help cells grow, divide, and stay alive are called oncogenes.
• Genes that keep cell growth in check, repair mistakes in DNA, or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA mutations (or other types of changes) that keep oncogenes turned on, or that turn off tumor suppressor genes. These types of gene changes can lead to cells growing out of control. Changes in several different genes are usually needed for a cell to become a cancer cell.

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). In some cases, these acquired mutations seem to happen randomly within a cell, without having a clear cause. In other cases, they likely happen as the result of exposure to an outside cause.

For example, ultraviolet (UV) rays are clearly a major cause of melanoma. UV rays can damage the DNA in skin cells. Sometimes this damage 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.

Most UV rays come from sunlight, but some can come from man-made sources such as tanning beds. Some DNA damage from UV exposure might happen in the few years before the cancer appears, but much of it could be from exposures that happened many years earlier. 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.)

Some melanomas occur in parts of the body that are rarely exposed to sunlight. These 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) orCDK4 that prevent them from doing their normal job of controlling cell growth. This could eventually lead to cancer.

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, several drugs that specifically target cells with changes in the BRAF gene are now used to treat advanced melanomas with these changes (see Targeted Therapy for Melanoma Skin Cancer).