Melanoma and genetics

ALSO KNOWN AS: Cutaneous melanoma; malignant melanoma

DEFINITION: Melanoma is a cancer that affects skin cells called "melanocytes." These cells produce skin color; they also give moles their dark color. Under normal conditions, moles are benign skin tumors, which means they are noncancerous. Sometimes a mole can develop into melanoma. A new mole may also be an early melanoma. Though less common than other types of cancer, melanoma is particularly dangerous and much more likely to spread to other parts of the body.

Risk Factors

Individuals who have certain types of moles called "dysplastic nevi," or atypical moles (which look similar to melanoma), and who have large dysplastic nevi present at birth are at increased risk of developing melanoma. Individuals are also at increased risk in early adulthood or later in life, if they are white, and if they have fair skin, red or blond hair, light-colored eyes, and family members with melanoma. Other risk factors include excessive skin exposure to the sun without protective clothing or sunscreen and a suppressed immune system.

Etiology and Genetics

The vast majority of melanomas result from chance mutational events that occur in dividing skin cells in adults. According to the American Cancer Society (2022), only about 10 percent of melanoma cases are familial, the rest being sporadic (nonfamilial). Several genes are known (or suspected) in which mutations may increase the tendency of an individual to develop melanoma, but the disease itself is not inherited.

Inherited mutations in the CDKN2A gene have been identified in about 35 to 40 percent of those families in which two or more closely related members have developed melanoma, as reported by the National Cancer Institute in 2022. Located on the short arm of chromosome 9 at position 9p21, this gene encodes a protein known as cyclin-dependent kinase inhibitor 2A, which is an important regulator of cell division. Some investigators suggest that between 58 percent and 91 percent of people with deleterious mutations in CDKN2A will develop melanoma by age 80, and they also have an 11 to 17 percent risk for developing pancreatic cancer, according to the National Cancer Institute. The CDK4 gene (at position 12q13) also specifies a protein that regulates cell division, and some mutations in this gene also result in an increased risk for developing melanoma.

The genes MC1R, MITF, BAP1, POT1, ACD, TERF2IP, and TERT also play a role in melanoma predisposition, but these, together with CDKN2A and CDK4, only account for approximately 45 percent of familial melanoma cases, according to a 2021 study by Kailos Genetics. The genetics underlying the remaining 55 percent of cases are not yet understood.

Other genes that play a role in hair and skin color and sensitivity to ultraviolet radiation are MC1R (at position 16q24.3), TYR (at position 11q14-q21), TYRP1 (at position 9p23), and ASIP (at position 20q11.2-q12). Mutations in each of these genes can cause an increased susceptibility to melanoma, although the risk increase is considerably less than what was noted for the CDKN2A and CDK4 genes. A 2009 genome-wide association study published in Nature Genetics identified MTAP (also on 9p21) and PLA2G6 (on 22q13.1) as other possible susceptibility genes. A report published in 2009 suggests that mutations in the MDM2 gene (at position 12q14.3–q15) can increase the risk of women (but not men) to develop melanoma in early adulthood. According to a 2011 literature review by J. H. Silva et al. in Clinics, mutations to the BRAF gene (at position 7q34) have been associated with dysplastic nevi and melanomas, especially those that are fast growing. In 2012, the National Institute of Arthritis and Musculoskeletal and Skin Diseases reported that the E318K mutation to the MITF gene poses an intermediate risk for carriers, as it is twice as common among populations with melanoma as in the general population. Finally, the National Cancer Institute stated in 2014 that the BRCA-associated protein 1 appears to play a role in the development of melanomas of the eye.

Symptoms

Melanomas are not usually painful. At first, they often have no symptoms. The first sign is often a change in the size, shape, color, or feel of an existing mole. Melanomas may also appear as a new, dark, discolored, or abnormal mole. Most people have moles, and almost all moles are benign.

A mole may be a melanoma if it is unevenly shaped, with the shape of one half not matching the shape of the other half. Moles that have ragged edges and are notched, blurred, or irregular, with pigment that may spread into the surrounding skin, may also be melanomas, as may moles that are unevenly colored, with uneven shades of black, brown, or tan, and possibly even white, gray, pink, red, or blue. A mole may also be a melanoma if it changes size, usually growing larger, and is usually larger than the eraser of a pencil (five millimeters or one-quarter inch, as reported by J. H. Silva et al.). Additional signs of a melanoma may be a change in a mole’s texture, with the mole beginning to have fine scales and, in advanced cases, becoming hard or lumpy; and a mole that is bleeding, itching, or, in more advanced cases, oozing or bleeding.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms and medical history, and a physical exam will be done. The doctor will look at a patient’s skin and moles. A biopsy will be taken of certain moles. Other moles will be watched over time.

The doctor may also examine lymph nodes, which may be in the groin, underarm, neck, or areas near the suspicious mole. Enlarged lymph nodes may suggest the spread of melanoma. The doctor may need to remove a sample of lymph node tissue to test for cancer cells.

Treatment and Therapy

Once melanoma is found, tests are done to find out if the cancer has spread. Treatment depends on whether the cancer has spread.

Treatment may include surgery, in which the melanoma and some healthy tissue around it will be removed. If a large area of tissue is removed, a skin graft may be done. Lymph nodes near the tumor may also be removed.

Chemotherapy, a treatment that uses drugs to kill cancer cells, may be given in many forms, including pills, injections, and via a catheter. Biological therapy, which involves substances made by the body to increase or restore the body’s natural defenses against cancer, is another treatment option. Examples of biological therapy include interferon, interleukin 2, and melanoma vaccines.

Radiation therapy is the use of radiation to kill cancer cells and shrink tumors. This is not a cure for melanoma, and it is used in combination with other therapies.

In the 2020s, BioNTech's BNT111 cancer vaccine emerged as a potentially effective immunotherapy treatment for some types of melanoma. As reported in 2024, researchers conducting a clinical trial started in 2021 found that patients with advanced melanoma experienced positive topline results after undergoing intravenously administered BNT111 in combination with the anti-PD-1 monoclonal antibody cemiplimab.

Prevention and Outcomes

Individuals can reduce their chances of getting melanoma if they avoid spending too much time in the sun. They should protect their skin from the sun; for example, they can wear shirts, wide-brimmed hats, and sunglasses. They should also use a sunscreen with a sun protection factor (SPF) of at least 15. Individuals should avoid exposing their skin to the sun between the hours of 10:00 A.M. and 2:00 P.M. (standard time) and 11:00 A.M. and 3:00 P.M. (daylight saving time), and they should avoid sun lamps and tanning booths.

In order to find melanoma in its early stages, individuals should see their doctors if they think they have this disease. Individuals who have many moles or have a family history of melanoma should have their skin checked regularly for changes in moles. Individuals should also ask their doctors to show them how to do a skin self-exam.

Bibliography

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