FAMILIAL MALIGNANT MELANOMA

October 14, 2009 — For the first time, guidelines have been proposed for genetic counseling and possible testing for individuals who have a hereditary pattern of malignant melanoma in themselves or in their families.

The guidelines for hereditary or familial melanoma, which accounts for 5% to 10% of all melanoma cases, were published online in the October issue of the Journal of the American Academy of Dermatology.

The guideline authors recommend that families or individuals who have a hereditary pattern of melanoma meet with a genetics counselor. The indicators of a hereditary pattern are 3 or more primary melanomas, or at least 1 case of melanoma and 2 or more other diagnoses of melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family.

Affected individuals might also want to take the next step: getting tested to determine if they have mutations of cyclin-dependent kinase inhibitor 2A (CDKN2A).

Up to 40% of hereditary melanoma cases have CDKN2A mutations, which are associated with an increased risk for pancreatic cancer, write the international team of guideline authors, led by Sancy Leachman, MD, PhD, from the Huntsman Cancer Institute of the University of Utah in Provo.

However, there are no data to support the idea that counseling and testing decrease the incidence of melanoma or improve outcomes, said Dr. Leachman.

"It is somewhat difficult to say that we have reduced the rate of melanoma development in these patients by providing them with the test report," he said, noting that inherited melanoma is a "rare disease" and not easily studied.

Hereditary melanoma can develop with or without unhealthy amounts of time in the sun, Dr. Leachman explained to Medscape Oncology. In individuals who carry the CDKN2A mutation, the risk for melanoma is "very high, regardless of whether excess sun exposure occurs or not," he said.

These guidelines are best suited for areas with "moderate to high melanoma incidence," such as the United States and the Netherlands, Dr. Leachman said.

However, in areas of high incidence, such as Australia, the baseline rate of melanoma is so high that 3 melanomas in the family would not necessarily suggest a hereditary pattern, she added.

Therefore, the guidelines are a "framework" for clinicians around the world to use in identifying cases of hereditary melanoma because the incidence of melanoma and penetrance of CDKN2A mutations varies from country to country, write the authors.

Benefits of Genetic Testing

There are a number of benefits to knowing whether you are a CDKN2A mutation carrier or not, Dr. Leachman explained.

"It provides knowledge to improve lifestyle choices and allows for selection of hobbies and professions that limit outdoor requirement," she said.

According to Dr. Leachman, the testing also allows individuals who are at risk for pancreatic cancer to be screened through research protocols and permits enrollment in research protocols for hereditary melanoma. Another consequence of testing is that it enhances compliance with recommendations for photoprotection in carriers and for self-skin examination and total body skin surveillance.

CDKN2A testing is imperfect because only 40% of hereditary melanomas have the mutation.

A total of "60% of the patients with a hereditary pattern of melanoma will have a negative test result that suggests the cause of their hereditary pattern is due to some other yet-to-be-identified reason, likely genetic or epigenetic," said Dr. Leachman.

There are currently 5 laboratories in the United States that perform CDKN2A testing. Dr. Leachman recommends that oncologists get in touch with the labs or develop a relationship with a genetics counselor who is familiar with the CDKN2A testing.

Recommendations Vary by General Population Rate

The counseling recommendations in the paper are based on a literature review of malignant melanoma and CDKN2A, in which higher rates of CDKN2A positivity were found in certain individuals and families.

For instance, in one study, the Genes and Environment and Melanoma Study Group, the likelihood of a CDKN2A mutation in an individual with 2 or more primary melanomas was 2%, but increased to 7% if a family history was present.

The likelihood of detecting a CDKN2A mutation depends greatly on the population being studied, add the authors.

In geographic areas with higher background rates of melanoma, there is a greater likelihood of having multiple family members with melanoma or multiple primary melanomas caused by reasons other than a CDKN2A mutation, they write.

However, "melanoma penetrance in CDKN2A mutation carriers" is also higher in areas with high background rates of melanoma, indicating a "potential interaction between CDKN2A and the other predisposing factors for melanoma in these areas," they hypothesize.

There is no absolute, single guideline for genetic testing worldwide because of the variability in the background incidence of melanoma and the penetrance of CDKN2A mutations among different countries, say the authors.

For instance, in areas of low melanoma incidence, 2 melanomas in an individual and/or any pancreatic cancer events in a family might be sufficient to consider a genetics referral, according to Dr. Leachman and colleagues.

Dr. Leachman reports receiving honoraria in the past from Myriad Genetic Laboratories, which provides CDKN2A testing.

J Am Acad Dermatol. 2009;61:677.e1-14. Abstract