The Genetics of Melanoma

How Genetics Can Play a Role in Melanoma

What Are Genes and What Do They Do?

  • Genes are specific sections of the DNA that are used by cells as a template to direct the creation of a protein. Each gene creates one protein. Genes in the DNA are packaged tightly together into structures called chromosomes. Each person inherits two copies of each chromosome; one from the person’s father and one from the person’s mother.
  • Each gene is made up of a unique sequence of DNA.
  • DNA contains the information to control how each cell of the human body functions, including its rate of growth, how often it divides, when it should live, and when it should die.

How Do They Do That?

Genes control cell functions by producing proteins that carry out specific tasks for the cell. These proteins act as messengers in the cell. It is essential that each gene have the correct instructions or “code” for making its protein so that the protein can perform the proper function for the cell.

What Role Do Genes Play in Melanoma?

Scientists now know that the development of cancer probably begins when one or more genes in a cell become damaged or missing (mutated). A mutated gene may result in the formation of an abnormal protein or no protein at all. As a result, the normal function in the cell is disrupted and the cell does may act inappropriately. Most melanomas (about 90%) are caused by damage to the genes which occurs by chance exposure to environmental agents (like ultraviolet light) after a person is born.

Melanoma is not inherited. Susceptibility to melanoma is inherited. Genetic susceptibility to melanoma occurs when specific gene mutations are passed from generation to generation. Many people who inherit the susceptibility never develop melanoma.

What Are the Chances of My Inheriting a Mutated Gene?

Genes are packaged onto chromosomes. A person inherits two copies of each chromosome; one from the person’s father and one from the person’s mother. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. This mutation does not mean that the individual will get melanoma, but it does increase the risk of developing a melanoma specific to this mutation.

What Is My Risk for Melanoma?

The average lifetime risk to develop a melanoma is almost 2%. The risk for men and women is different. Currently the average lifetime risk for women is 1.6% and the average lifetime risk for men is 2.3%.

How Do I Find Out If I Have an Inherited Genetic Mutation That Increases My Risk of Melanoma?

Only genetic testing can determine whether a person has a genetic mutation. Currently, scientists suggest that families with multiple cases of melanoma consider participating in genetic research studies, so that more can be learned about the influence of genetic mutations on the risk of melanoma. Scientists have identified several genes that are associated with an increased risk of melanoma. However, more genes have yet to be found. Even in families with several people with melanoma, genetic testing fails to reveal the mutated gene because it’s identity is not yet known.

How Do I Know If Melanoma Runs in My Family?

There are important signs that suggest possible cases of heritable melanoma, including:

  • One person developing two melanomas that are not related. (A second primary melanoma.)
  • More than two first-degree or three of any degree relationship in the family with melanoma and family members with both melanoma and pancreatic cancers.
  • Early age of onset and multiple nevi were once thought to be risk factors for having heritable melanoma. At this time, it is not felt that just having an early melanoma or multiple nevi increase one’s chances of having heritable melanoma sufficiently to warrant genetic testing.

Most experts strongly recommend that people concerned about their family history of melanoma first consult a genetic counselor. Genetic counselors are trained to assess the potential for hereditary cancer risk in a family and can identify appropriate genetic testing or research studies.

What Is a Person's Risk If Melanoma Runs in the Family?

If a person has one first-degree relative with melanoma, his or her risk of developing melanoma is two to three times greater than the general population risk. The risk is MUCH higher (30-70x) if there are multiple first-degree family members with melanoma. 1

Which Inherited Genetic Mutations Raise the Risk of Melanoma?

There are a growing number of genes thought to be associated with an increased risk of melanoma. However, more research is needed to better understand how these genes impact the risk of melanoma.

Mutations in at least three gene products have been linked to hereditary melanoma. Families with mutations in these genes may have multiple dysplastic nevi. Multiple dysplastic nevi is also sometimes called familial atypical multiple mole melanoma (FAMMM), dysplastic nevus syndrome (DNS), or atypical mole syndrome (AMS).

  1. The CDKN2A Gene
    Mutation in this gene (also called p16 and MST1) are thought to account for approximately 25% of hereditary melanoma cases. People who have mutations in the CDKN2A gene have a nearly 70% risk of developing melanoma during their lifetime, but the risk varies by geographic location. Some families with these mutations also have an increased risk (up to 17%) of developing pancreatic cancer. Pancreatic cancer, however, is much less frequent than melanoma in these families.The CDKN2A gene is called a tumor-suppressor gene. Tumor-suppressor genes make proteins that suppress tumor formation by limiting cell growth. Mutations in tumor-suppressor genes result in a loss of the ability to restrict tumor growth, and, as a result, cancer can develop. CDKN2A is a rather unique gene, in that it is the only gene known to produce two different proteins, p16 and p14ARF, depending on how the gene is “read.” Mutations affecting p16 are known to be associated with an increased risk of melanoma and pancreatic cancer. The cancer risk associated with mutations affecting p14ARF is not as well understood, although there is an increased risk for melanoma, and possibly other cancers, in a small number of families.
  2. The CDK4 Gene
    Mutations to this gene are responsible for an increased risk of melanoma in a very small number of families. The cancer risks associated with mutations in CDK4 are thought to be similar to those in families with mutations in CDKN2A. The CDK4 gene is called a proto-oncogene. Proto-oncogenes make proteins that promote normal cell growth. Mutations in proto-oncogenes result in too much cell growth and can lead to cancer. Genetic testing for mutations in the CDK4 gene is not available. Based on limited data, the clinical characteristics of melanomas occurring in families with CDK4 mutations are quite similar to those in families with CDKN2A mutations.
  3. Chromosome 1 (1p22)
    Recently, a third area on this chromosome has been shown to possibly contain another melanoma susceptibility gene that has not yet been identified. There is also evidence that additional genes associated with hereditary melanoma exist. This is a very active area of research.

What Do the Experts Think?

Genetic testing for mutations in CDKN2A is available, but the Association of Surgical and Clinical Oncologists’ (ASCO) Task Force on Genetic Testing recommends that such testing not be routinely performed outside of a research setting since researchers do not fully understand the implications of certain types of mutations. In addition, several types of melanoma that run in families do not yet have clearly defined genetic causes. ASCO bases its clinical recommendations for identifying melanoma risk on family history, skin type, and environmental factors regardless of the presence or absence of known mutations. Testing for genetic susceptibility remains a source of hot debate among researchers, some of whom feel that there would be a benefit for patients who are tested, and others who do not agree. There are currently studies underway to assess the impact for good or bad that comes when patients are tested for genetic susceptibility to melanoma.

What Should I Do If I Am at Risk?

People at risk for hereditary melanoma should examine their skin carefully each month to look for changes in the appearance of moles. Screening should begin by age 10 in children at risk. Skin examinations by a trained health care provider should be performed yearly or more frequently if necessary.


1. Goldstein AM Dermatol Clin 13: 605-612, 1995.

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