Introduction to Cancer Genetics and Melanoma

Patient's Guide to the Genes Involved in Melanoma Skin Cancer

Medical researcher in laboratory checking genes
Eva Plevier/Stocksy United

Understanding cancer genetics and how it plays a part in melanoma may sound like a daunting task. But taking the time to do just that can help you better understand your risk -- and what you can do about it.

Cancer Genetics

Cancer begins when one or more genes in a cell mutate (change from their normal form). This either creates an abnormal protein or no protein at all, both of which cause mutated cells to multiply uncontrollably.

A large number of genes are being investigated for their role in melanoma, including inherited genes and genetic defects that are acquired due to environment factors, such as excessive sun exposure. So far, specific genetic variations account for only 1% of all melanoma diagnoses, although a 2009 study of twins with melanoma showed that 55% of a person's total melanoma risk may be due to genetic factors. Research in this complicated area is still in its infancy, but hopes are high that in the near future, genetic tests will help guide melanoma screening, diagnosis, and treatment.

Inherited Gene Mutations in Melanoma

Examples of gene mutations that are passed down from parent to child include the following:

CDKN2A - Mutations in this regulator of cell division are the most common causes of inherited melanoma. These mutations, however, are still very uncommon overall and can also appear in non-inherited cases of melanoma.

People with familial melanoma often have a large number of irregularly shaped moles (dysplastic nevi) and are diagnosed with melanoma at a relatively young age (35 to 40 years old). Since 70% of people who have mutations in the CDKN2A gene will develop melanoma during their lifetime, commercial tests have been developed for CDKN2A, although it is not clear if knowing the results of the test will benefit people carrying the gene.

A related but even rarer mutation is in the CDK4 gene, which also controls when cells divide and increase the risk of developing melanoma.

MC1R - Increasing evidence is showing that the greater the number of variations in a gene called MC1R (melanocortin-1 receptor), 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. People who have olive and darker skin and who carry one or more variations of the gene have a higher than average risk for melanoma. Nonetheless, having the MC1R mutation carries a more moderate risk than the CDKN2A or CDK4 mutations. Recently, other genes involved with skin pigment have been identified that may also increase susceptibility to melanoma, including TYR (tyrosinase), TYRP1 (TYR-related protein 1), and ASIP (agouti signaling protein).

MDM2 - The MDM2 genetic variant appears in the gene's "promoter," a kind of power switch that determines when the gene is turned on and how many copies are produced within a cell. Research published in 2009 showed that it predisposes women -- but not men -- to develop melanoma at a younger age (less than 50 years old). Having this mutation may be even more potent than other melanoma risk factors such as a history of blistering sunburns, fair skin, and freckling.

If you have a parent or sibling with melanoma, your risk of developing melanoma is two to three times greater than the average person. However, the risk is still small, and in many cases, the defective gene won't be found. Nonetheless, most experts strongly recommend that people concerned about their family history of melanoma consult a genetic counselor and ask your doctor about participating in genetic research studies so that more can be learned about how genetic mutations influence the risk of melanoma. Minimally, people at risk for hereditary melanoma should practice sun safety and examine their skin carefully each month beginning at age 10 to look for changes in the appearance of moles.

Gene Mutations That Are Not Inherited

Gene mutations that aren't inherited but rather are acquired due to environmental factors such as the sun include:

BRAF - Studies have identified a non-inherited mutation in the BRAF gene that appears to be the most common event in the process that leads to melanoma; it has been observed in up to 66% of malignant melanomas. Researchers hope that drugs that block this gene may be an effective treatment strategy in the future.

P16 is a tumor suppressive gene that may be abnormal in some non-inherited cases of melanoma. Genetic mutations that regulate Ku70 and Ku80 proteins may disrupt processes that repair strands of DNA.

EGF - Researchers are studying mutations in a gene that makes a substance called epidermal growth factor (EGF). EGF plays a role in skin cell growth and wound healing, and it may account for many non-inherited cases of melanoma.

Fas - Mutations in genes that regulate Fas proteins, which are involved in a natural process of cell self-destruction called apoptosis, can cause melanoma cells to proliferate out of control.

The molecular processes that lead to the initial development and the metastasis of non-familial melanoma are extremely complex and are just beginning to be investigated. Literally, thousands of research reports about melanoma genetics have been published in just the last decade. These advancements will hopefully lead to the identification of much more accurate tests for the diagnosis and prognosis of melanoma, as well as more effective treatment targets for this devastating disease.


"The Genetics of Melanoma." ASCO. 26 February 2009.

Hocker TL, Singh MK, Tsao H. "Melanoma genetics and therapeutic approaches in the 21st century: moving from the bench side to the bedside." J Invest Dermatol 2008 128(11):2575-95. 26 February 2009.

Lin J, Hocker TL, Singh M, Tsao H. "Genetics of Melanoma Predisposition." Br J Dermatol 2008 159(2):286-9. 26 February 2009.

"Familial melanoma." Melanoma Molecular Map Project. 27 February 2009.

Firoz EF, Warycha M, Zakrzewski J, et al. Association of MDM2 SNP309, the age of onset, and gender in cutaneous melanoma. Clin Cancer Res. 2009 Apr 1;15(7):2573-80.

Shekar SN, Duffy DL, Youl P, et al. A Population-Based Study of Australian Twins with Melanoma Suggests a Strong Genetic Contribution to Liability. J Invest Dermatol. 9 April 2009.

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