What is familial malignant melanoma? Who is at risk?

What is familial melanoma?

Familial malignant melanoma is a term describing families in which two or more first-degree relatives, usually parents, siblings or children, have melanoma, a type of skin cancer.

• Approximately 8% of people newly diagnosed with melanoma have a first-degree relative with melanoma.
• Approximately 1% to 2% of people with melanoma have two or more close relatives with melanoma.

Individuals in melanoma-prone families often have moles called dysplastic nevi. Dysplastic nevi are large, flat, irregular, asymmetrical moles with variable colors. Although generally found on sun-exposed skin, they can also occur in areas not exposed to the sun. Moles should be monitored very carefully for any changes in size, shape and color that may indicate cancer.

The average age at melanoma diagnosis is 30 in people with familial melanoma, compared with an average age of 50 in the general population.

What causes familial melanoma?

Familial melanoma is an inherited condition. This means that melanoma risk can be passed from generation to generation in a family. To date, the genes CDKN2A and CDK4 have been identified as two genes in which mutations are associated with familial melanoma. A mutation in either of these genes increases melanoma risk. However, changes in these two genes account for only a small percentage of familial melanoma.

CDKN2A affects two proteins called p16 and p14ARF, which have different functions. Both CDKN2A and CDK4 play important roles in controlling cell division. Studies of families with CDKN2A gene mutations from Europe, North America and Australia have shown that melanoma risk varies by geographical region. The reasons for these differences are not fully understood. There may be differences in the amount of sun exposure, other individual or genetic differences, or a combination of these factors. In addition, pancreatic cancer risk may also be increased.

In melanoma-prone families with known genetic mutations, dysplastic nevi (moles) and sun exposure are independent risk factors for melanoma. Recently, another gene called MC1R was found to affect melanoma risk in people with and without CDKN2A gene mutations. MC1R is important in regulating pigment in the body, and variations have been associated with freckles and red hair.

Other inherited genes are associated with increased melanoma risk. For example, xeroderma pigmentosum (XP) is a rare disease in which people have a mutation in a gene required to repair DNA damage caused by ultraviolet radiation (sunlight). People with XP have extremely high rates of skin cancer, including melanoma. The so-called hereditary breast cancer gene BRCA2 is also associated with a small increase in melanoma risk.

Researchers believe that other, as yet unidentified genes increase melanoma risk. Research to learn more about familial melanoma is ongoing.

How is familial melanoma passed on to later generations?

Normally, each cell contains 2 gene copies, one inherited from the mother and one from the father. Familial melanoma follows an autosomal dominant inheritance pattern, and a mutation in only one copy of a gene is sufficient for it to occur.

This means that a parent with a gene mutation can pass a copy of either the normal gene or the mutated gene to their child. Therefore, a child with a parent carrying the mutation has a 50% chance of inheriting it.

The brother, sister or parent of a person with the mutation also has a 50% chance of carrying the same mutation. However, if the parents test negative for the mutation (no mutation is found in their test results), the risk to siblings is significantly reduced, although their risk may still be higher than average.

Options are available for people with an inherited cancer syndrome who want to have children. Preimplantation genetic diagnosis (PGT), performed in conjunction with in vitro fertilization (IVF), is a medical procedure that may allow people to have a child without passing on a specific gene mutation. The woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size (approximately 8 cells), 1 cell is removed and tested for the inherited condition in question. Parents can then choose to transfer embryos without the mutation into the woman’s uterus. PGT has been used for more than twenty years to prevent various inherited cancer predisposition syndromes. However, it is a complex procedure requiring consideration of financial, physical and emotional factors before starting PGT.

How common is familial melanoma?

Most melanoma cases are sporadic, meaning that, according to current knowledge, they occur by chance. The number of people with inherited melanoma risk is unknown but is thought to be low. It is estimated that approximately 8% of people with melanoma have a first-degree relative with melanoma, and 1% to 2% of people with melanoma have 2 or more close relatives with melanoma.

2020 Turkey Cancer Statistics states that 1756 people in Turkey were diagnosed with melanoma.

How is familial melanoma diagnosed?

Familial melanoma is suspected when two or more close relatives have invasive melanoma (if it has spread to other parts of the body). Sporadic melanoma is more common in areas with greater sun exposure, such as the United States, South America or Australia, so familial melanoma is not diagnosed in these regions unless three or more close relatives have invasive melanoma. Familial melanoma may also be suspected if a single family member has more than one melanoma.

To detect mutations in the CDKN2A gene, genetic tests are available. However, genetic test results are unlikely to change screening recommendations or clinical care for people with melanoma or an extensive family history of melanoma. Most families with familial melanoma may not even have an identified genetic mutation. Other genes that may be involved can be found through evaluation by a genetic counselor or doctor.

What are the estimated cancer risks associated with familial melanoma?

A person with inherited melanoma risk has a greatly increased lifetime risk of developing melanoma.

Families with familial melanoma and CDKN2A mutations also have an increased risk of pancreatic cancer, although this is relatively rare. Brain tumors have also been reported in a few families.

People with xeroderma pigmentosum (XP) also have an increased risk of other skin cancers, such as squamous and basal cell carcinomas. Women with BRCA2 mutations also have an increased risk of breast and ovarian cancer, men have an increased risk of prostate cancer, and both men and women have an increased risk of pancreatic cancer.

What are the early detection / screening options for familial melanoma?

Anyone with a parent, sibling or child with melanoma should be monitored carefully for melanoma. People with melanoma should have thorough skin examinations every 3 to 6 months by a healthcare professional specializing in skin diseases to monitor for any changes in shape, size or color. Dermatologists may photograph the skin and moles, known as mole mapping, or view moles using a handheld device called a dermatoscope. This process can help show changes over time. Any suspicious mole or other skin change should be removed by a doctor so that the tissue can be analyzed under a microscope.

In families known or strongly suspected to have familial melanoma, children should begin screening before age 10. Family members should also perform regular self-examinations to notice skin changes. Because of the high risk of multiple melanomas, people with familial melanoma should avoid sun exposure and take precautions to protect themselves when outdoors.

Screening recommendations may change over time as new technologies are developed and more is learned about familial melanoma. You can talk to your doctor about appropriate screening tests.

Questions to ask your healthcare team

If you are concerned about your cancer risk, you can talk to your healthcare team. It may be helpful to bring someone to your appointments to take notes. You can ask your healthcare team the following questions:

• What is my melanoma risk?
• What can I do to reduce my cancer risk?
• What are my options for cancer screening?

If you are concerned about your family history and think you or other family members may have familial melanoma, you can ask the following questions:

• Does my family history increase my melanoma risk?
• Do my family and I need a cancer risk assessment?
• Would you refer my family and me to a genetic counselor or another genetics specialist?
• Should my family or I consider genetic testing?
• What preventive measures do you recommend for my family and me?