Specialists warn about familial melanoma syndrome

People with relatives who have had a melanoma have a 30 times greater risk of developing the disease and require continuous monitoring, warned doctors during the World Congress on Cancers of the Skin.

By Karina Toledo

Agência FAPESP – People with a family history of melanoma have a 30 times greater risk of developing the disease and need continuous dermatological monitoring for early diagnosis, warned specialists at the 14th World Congress on Cancers of the Skin held in São Paulo in August.

“Between 5% and 10% of all cases of melanoma are related to hereditary genetic mutations, which make these patients and their family members more susceptible to developing tumors. This is what we call the familial melanoma syndrome,” explains dermatologist Susan Puig of the Hospital Clinic Barcelona in Spain.

Puig leads a group of Latin American researchers linked to GenoMEL, an international consortium headquartered in England. One of the group’s objectives is to identify mutations that increase patient susceptibility to this type of cancer and establishes protocols for monitoring high-risk patients.

“In addition to family history, there are other factors that we use as markers to measure risk. People with more than 100 moles or atypical moles, that is, moles with irregular edges or of more than one color, are more likely to develop the disease,” says Puig.

If, in addition to these characteristics, the patient has a history of melanoma, the probability of developing another tumor is 500 times greater than that in the general population. If genetic tests are positive for one of the known mutations, the probability is 1000 times greater.

“If these high risk patients are not identified and adequately treated, they can die of melanoma. However, with early diagnosis, mortality is essentially zero,” he affirmed.

According to Gilles Landman, a professor at Universidade Federal de São Paulo (UNIFESP), the odds of curing a melanoma that is less than 1 millimeter (mm) deep are 90%. “However, for cases in which the lesion is more than 4 mm deep when it is diagnosed, 50% of patients die within five years,” he said.

In 2007, when Landman was working at A.C. Camargo, he was invited by GenoMEL to participate in their investigations of familial melanoma. “ The consortium had been researching genetic mutations in Europe, the United States and Australia, and they also wanted to know the genomic profile of patients in Latin America,” he explained.

With FAPESP funding under the Regular Research Awards program, Landman assembled a group of professionals with varied specializations, identified 50 families with familial melanoma syndrome and coordinated the genetic sequencing of this group.

“We selected patients in treatment for melanoma who had at least one first or second degree relative with the disease. We also included patients with a family history of pancreatic cancer, brain cancer or ocular melanoma because these tumors are associated with the syndrome,” explained Landman.

The study also included patients with multiple melanomas, even if they did not have a family history of the disease. “When a person develops several tumors, he or she is very likely to have a mutation that makes him or her more susceptible to the disease,” said the researcher.

Discovering the genes

According to Puig, five genetic mutations related to familial melanoma syndrome have already been described, but scientists believe that there are still many unknown and uncommon mutations.

“Among the known mutations, the most important occurs in the CDKN2A gene. This mutation is found in approximately 10% to 15% of the families with more than two cases of melanoma. The rate rises to 25% when there are more than three cases in the family, 50% of families with four cases and to 70% of families with at least five cases,” explains Puig.

The main objective of the study coordinated by Landman is to measure the frequency of this mutation in a group of patients with familial melanoma. “This gene encodes a protein called p16, which functions to block cellular proliferation. When this protein is mutated, it does not play this role adequately,” explains the researcher.

Among the 50 families studied, only nine presented a mutation of the CDKN2A gene. The study found eight cases among 32 patients with a history of familial melanoma and one case among the 18 patients with multiple melanomas.

“This shows that the problem is much more complex than it appears. Many additional studies will be needed in order to discover the other genes involved,” says Landman.

After the sequencing project was completed, Hospital A. C. Camargo continued working with familial melanoma patients, creating Brazil’s first center to serve patients with this profile.

“In addition to these 50 families that returned to us after participating in the study, we located another 68 with the syndrome. We are monitoring the melanoma patients and their relatives, especially, immediate family,” says Bianca Sá, coordinator of the center.

Patients at the center must answer a questionnaire about sun exposure and cancer in the family. Additionally, the center photographs and maps every mole on the patient’s body. “At least once a year they must return to repeat the exam, and new photos are taken and compared to the previous photos,” says Sá.

Another test, which was standardized during the GenoMEL study, looks for the mutation in the CDKN2A gene. This test is also available at the hospital (for a fee), but its use outside the context of the study is still controversial.

“The big question is: how will the results change the life of the patient? People with melanoma have to be closely monitored because the risk of a new tumor is great. For them, however, this monitoring changes very little in their day-to-day lives Perhaps it would be interesting to test their children. If the results are positive, they could be given orientation to prevent cancer,” Sá suggests.

However, as there are still many unknown mutations, says Landman, one negative result does not mean that the person does not have the syndrome.

“Furthermore, this gene does not have what we call complete penetrance. This means that only 67% of carriers of this mutation will develop melanoma before age 80. Not everyone. I don’t know if it is useful to leave the patient in doubt,” he said.