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Genetic testing for melanoma risk


Patients who carry a high-penetrance melanoma predisposition gene can often benefit from screening for other cancers. Patients who receive a positive genetic test result are more likely to embrace prevention and detection measures. A new “Rules of Three” proposes a point-based guideline to help determine who should be referred for genetic counseling and testing.

Dr. LeachmanThe identification of patients that should receive genetic testing and the specific genetic tests that should be ordered for those patients are evolving, as the understanding of predisposition to melanoma and the relationship between melanoma and other cancer risk improves.

“Genetic testing, although incredibly helpful for a small number of people, is not something that is frequently indicated for melanoma patients,” says Sancy Leachman, M.D., Ph.D., a professor and chair of dermatology at Oregon Health and Science University in Portland. “The people who are good candidates for melanoma genetic testing are very few, relative to the entire population of melanoma cases.”

In an interview with Dermatology Times following her presentation on genetic testing at the American Academy of Dermatology (AAD) annual meeting in March, Dr. Leachman says that one of the major benefits of melanoma genetic testing is being able to identify people at risk.

“Identifying the individuals who carry a causal melanoma mutation allows these patients to be screened for other cancers, like ocular melanoma or pancreatic cancer, before those cancers develop,” Dr. Leachman says. “It is important to catch these cancers at their earliest stage, before they become life-threatening.”

Melanoma risk may mean risks for other cancers

For example, a patient who carries a cyclin-dependent kinase inhibitor 2A (p16) mutation “is not only at risk for melanoma, but they may also be at risk to a lesser extent, but still at a relatively high rate, for pancreatic cancer,” Dr. Leachman states.

A p16 mutation-carrying patient has a roughly 70% lifetime risk of developing melanoma, but also about a 20% lifetime risk of developing pancreatic cancer.

“However, pancreatic cancer requires a different screening protocol,” Dr. Leachman says. An individual with a p16 mutation “would benefit from screening for pancreatic cancer, too, because it is a lethal cancer that you would almost never detect early enough to be life-saving if you were not screening for it.”

Patients who receive a positive genetic test report are also more likely to participate in its prevention and early detection activities, thus enhancing compliance with medical recommendations for photoprotection and for self-screening and for physician visits. 

Tailored screening is another advantage of melanoma genetic testing. For instance, if a patient has a mutation in the BAB1 gene, this patient would not have an increased risk of pancreatic cancer, but would have an increased risk for ocular melanoma and mesothelioma, and screening for the right cancers can be performed.

Next: Who to screen, what are the risks


Who to screen, what are the risks

On the other hand, the risks of melanoma genetic testing “have proven to be fairly minor,” Dr. Leachman notes. “People thought initially that genetic testing might cause fatalism, but it does not in most people. There was also a worry that there would be a lot of anxiety or depression or other psychological downsides; however, that has not been proven to be the case. People are very resilient. They do not let a positive test keep them down for long.”

Nonetheless, there is a risk that people who test negatively will have a false sense of security and still develop melanoma, even though they do not carry the gene, because they were emboldened to neglect preventative measures.

Patients who need to be panel tested for melanoma are those that meet the updated “Rules of Three”: at least three invasive melanomas in blood relatives; or at least three melanomas in a single individual; or at least three melanomas within a family + pancreatic cancer or other cancers that add up to a total of three points. 

Dr. Leachman recommends that a melanoma primary gene panel consist of BAP1, CDK4, CDKN2A, MITF and POT1.

A corresponding organ specific panel for breast, colon, ovarian, pancreatic or prostate cancer should also be obtained, if the risk is justified.

 “Sequence-based testing through a certified laboratory is incredibly accurate,” says Dr. Leachman, who is also director of the melanoma and skin cancer program at Knight Cancer Institute in Portland. “We know which genes have mutations and what the mutations are; however, the effects that those mutations will have on a given individual are not so clear.”

Follow up care

Genetic counselors engage with patients to create follow-up recommendations for skin and other cancer subtypes, depending on the results of the genetic test.

Dr. Leachman is the lead author of an article in the March edition of Cancer Metastasis Review (doi: 10.1016/j.jaad.2009.03.016) that discusses who to test, which genes to test and what kind of follow-up to suggest, if actionable mutations are found.

“Ultimately, we will have the ability to perform whole genome sequencing on patients to identify every mutation they carry, but for now, this technology is plagued by the identification of too many mutations for which no clinically useful data is known, now called variants of uncertain significance,” Dr. Leachman explains. “Soon we will better understand what is a driver of cancer as opposed to what is merely a bystander. Once we reach this point, we can provide very precise, individual, specific recommendations like we have never been able to do before.”

Dr. Leachman has been a medical advisor for Myriad Genetic Laboratories and Castle Biosciences.

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