Hereditary melanoma

How common is melanoma skin cancer?1

Melanoma skin cancer (referred to as melanoma from here on) is the sixth most common cancer type in Swedish men and the fifth most common in Swedish women. It is the most rapidly increasing cancer in Sweden, with a 5% increase in cases each year. The median age of diagnosis is 65 years of age for women and 69 for men.

What causes melanoma?1

About 90 to 95% of all melanoma is caused by DNA damage, which can occur during DNA replication or be due to environmental factors, such as sun exposure. DNA damage occurs all the time and most of the time it is repaired. But with age comes an accumulation of DNA damage, and in turn a higher likelihood that a normal cell transforms into a cancer cell. Age is therefore the leading risk factor for cancer.

The remaining 5 to 10% of all melanoma is explained by hereditary factors. The impact of hereditary factors on the risk of developing melanoma can range from small to very large. What they have in common is that individuals with a hereditary risk of cancer are born with one high-risk genetic variant or several low-risk DNA variants that are present in all cells. These variants often affect proteins involved in DNA repair or in other ways protect cells from becoming cancer cells. Therefore, the ability to protect cells from becoming cancer cells may be impaired which results in DNA damage. Normal cells in individuals with a hereditary risk of cancer thus have a higher probability of becoming cancer cells.

Underlying genetic factors

One or more individuals with melanoma in a family is enough to suspect an underlying hereditary cause. The following criteria are used in the health care system to identify families, or individuals, with familial melanoma:

  • Families with two first-degree* relatives who have been diagnosed with melanoma (invasive or in situ), one of which before 55 years of age.

  • Families with two or three first-*, second-**, or third-degree*** relatives who combined have been diagnosed with three or more melanomas (invasive or in situ).

  • One individual with three or more individual melanomas (invasive or in situ), where the first was diagnosed before 55 years of age.

  • Families with cases of melanoma (invasive or in situ) and pancreatic cancer in the same branch of the family. The individuals must be first-*, second-**, or third-degree*** relatives to each other.

To put it simply, early-onset melanoma, several cases in the same branch of the family, melanoma and pancreatic cancer in the same branch of the family, or one individual with several melanomas may indicate heredity.

Families that fulfill these criteria are classified as having familial melanoma. In about 10% of these families an underlying pathogenic variant is found in the CDKN2A gene. Forty families in Sweden are known to have a pathogenic variant in CDKN2A. Most of them carry the same variant (p.Arg112dup) due to a common ancestor. Individuals that carry a pathogenic variant in CDKN2A get diagnoses much earlier than in the general population (median age 39 years).

Pathogenic variants in CDKN2A also increase risk of other types of cancer in addition to melanoma. Individuals with the p.Arg112dup variant have an high risk of pancreatic cancer as well as an increased risk of oral, lung, stomach, larynx, and throat cancer. At 80 years of age, 95% of all carriers of the p.Arg112dup variant will have been diagnosed with melanoma or some other type of cancer. Risk for other cancer types appear to increase after 30 years of age. Smokers have a higher risk for cancer in the airways and digestive organs as compared to non-smokers.

Four Swedish families have been diagnosed with eye and skin melanoma due to pathogenic variants in the BAP1 gene. Knowledge on BAP1 is still limited and its impact on cancer risk unknown.

Pathogenic variants in PTEN, BRCA2, RB1 and TP53 are also associated with an increased risk of melanoma.

In addition to the above-mentioned genes associated with a moderate to high risk of melanoma, there are variants in other genes that give a small increased risk of melanoma. These genes often have a role in pigmentation and are often associated with blue/grey/green eye color, blonde/red hair color as well as a lighter complexion and freckles.

Analysis of CDKN2A, BAP1, PTEN, BRCA2, RB1 and TP53 are included in the GeneMate® for hereditary cancer. The complete gene panel can be found at genemate.se.

Risk-reducing measures in healthy carriers of a CDKN2A variant

Below screening programs are recommended for individuals with a pathogenic variant in CDKN2A (full list of recommendations can be found here):

  • Yearly skin exams from age 18

  • Yearly medical exams by a specialist from about age 30

  • Yearly pancreatic cancer screening from about age 40

Carriers should also be informed of measures to prevent skin melanoma as well as how to examine the skin to identify changes in the skin. Smokers should be offered a smoking cessation program.

Risk-reducing measures for healthy relatives of a carrier of a CDKN2A variant

Family members of a carrier of a pathogenic variant have a small increased risk of melanoma even without being a carrier themselves. However, the risk for melanoma is not high enough to warrant screening. Non-carriers should however be informed of measures to prevent melanoma as well as how to examine the skin to identify changes in the skin.

Risk-reducing measures for carriers of a BAP1 variant

Individuals with a pathogenic variant in BAP1 are recommended yearly skin and eye screening as well as yearly screening of the kidneys.

Risk-reducing measures for families with familial melanoma but without a variant

As previously mentioned only a subset of the hereditary risk of melanoma can be assigned to a pathogenic variant. In most families (about 80-90%) the cause of the familial cancer is still unknown. What these families have in common is an increased risk of skin melanoma and an earlier age of onset (median age of 50 years). Apart from increased risk of squamous cell carcinoma, the risk of other cancer types does not appear to be increased.

Because of the increased risk of melanoma, family members who have themselves had melanoma and first-degree relatives should be offered skin exams (once or yearly). They should also be informed of measures to prevent melanoma as well as how to examine the skin to identify changes in the skin.

The GeneMate® test combines a genetic test with an assessment of your family’s cancer history, either of which can indicate an increased risk of familial melanoma. Therefore, it is important that you provide comprehensive information about your family’s cancer history (if available). We will help you get in contact with the appropriate care provider if cancer screening is motivated.

*First degree relative: Biological parents, siblings, and children of the index person

**Second degree relative: Biological grandparents, siblings of parents, children of siblings, and grandchildren of the index person.
***Third degree relatives: Biological cousins, great grandparents, siblings to grandparents, and children to grandchildren.

 

ORDER

 

Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology

References

  1. Nationellt vårdprogram hudmelanom – RCC kunskapsbanken. https://kunskapsbanken.cancercentrum.se/diagnoser/hudmelanom/. Published 2019-04-29, Accessed 2020-02-22.