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Mapped-out risk

Study identifies the genetic profile of Brazilian patients with a rare disease that causes a specific type of thyroid cancer

Medullary thyroid cancer cells, tumor related to MEN2 syndrome

Sciepro / Science Photo Library

A multicenter study identified the profile of the mutations that cause, among the Brazilian population, a rare hereditary syndrome known as multiple endocrine neoplasia type 2, or simply, MEN2, which affects on average one in every 80,000 people. In almost 100% of cases, the disease results in medullary thyroid cancer (MTC), which consists of malignant tumors that can cause death if not treated early. In fewer cases, other endocrine tumors may also appear, such as in the adrenal medulla and parathyroid glands. MEN2 is caused by different mutations in one gene, the RET. According to the study, which identified the variant of this gene that is present in 176 families who are connected to 554 patients with MTC, the more frequent mutations in the country are, in general, the same as those described in the European population. However, regional differences in the profile of the genetic changes were found, which could be a reflection of the blending of the Brazilian people, due to their European, indigenous, and African ancestries. The results of the study, which found 13 different types of mutations in this gene, were published in the March edition of the scientific magazine Endocrine Connections.

In order to establish a probable prognosis for the evolution of the tumor, it is fundamental to identify the mutation of the RET gene that causes MEN2 and, by extension, medullary thyroid cancer. “There is a relationship between the type of mutation and the clinical condition of the patients,” explains endocrinologist Rui Monteiro de Barros Maciel, from the Federal University of São Paulo (UNIFESP) and one of the coordinators of the study, which involved a consortium of 46 researchers from 18 of the country’s top institutions in the field. Some mutations lead to much earlier and more serious representations of the disease, requiring much faster intervention, while others express themselves in a milder way. The M918T mutation, for example, is classified as the highest risk and appears as the second most common among studied patients (almost 15% of families have this genetic mutation). For those with this mutation, the recommendation is to remove the thyroid immediately, even if there are no apparent tumors.

The most common mutation found in Brazilian patients, which was present in 43% of families in the study, is the C634, which also has higher risk of causing thyroid cancer, but with lower frequency than patients with the M918T. In the case of mutations with a milder manifestation, such as the V804, found in 12.5% of families in the study, the removal of the thyroid, which is considered necessary for all cases of MEN2, can be done later.

In addition to the degree of aggressiveness of the mutation being important to prevent the development of MTC, a delay in the diagnosis can also reduce the chances of a cure. “Many cases are diagnosed late, which contributes to mortality and death of patients,” confirms endocrinologist Ana Luiza Maia, head of the Thyroid Unit at the Hospital de Clínicas de Porto Alegre, connected with the Federal University of Rio Grande do Sul (UFRGS), which is the other coordinator of the study, called BrasMEN. The study was funded by the research support foundations of São Paulo and Rio Grande do Sul.

One of the most interesting pieces of data produced by the study is related to the prevalence in Brazil of mutation G533C, which was discovered by Maciel and his team in 2002. This alteration was present in 0.6% of participating families in the study, a frequency greater or equal to that found in countries in Europe, with one exception: Greece, where this mutation is more common. “We believe that other individuals living in Europe could present the same mutation due to the fact that the family in which we discovered this genetic alteration came from Barcelona, Spain, and emigrated to Brazil at the end of the nineteenth century,” recalls Maciel. In partnership with Greek researchers, Maciel and his colleagues determined that this mutation actually originated with the Hellenic peoples and then spread to the rest of continental Europe.

BrasMEN also made a discovery about the ancestry of the syndrome in Vale do Jaguaribe, Ceará. In this state, researchers found a rare mutation named M918V in some families. “At first, we thought it existed in isolated families, but the genetic study showed that all patients had a common ancestry, said Maciel. Mathematics studies indicated that mutation M918V stays with a local population for 15 generations, or more than 350 years. Historical surveys based on oral narratives, as well as the archives of birth and baptismal records, confirmed the existence of common ancestors who emigrated from Portugal to Brazil in 1700 and participated in the colonization of Ceará.

Genetic testing
For Maciel, the study of the RET gene can bring tranquility and improve quality of life for those carrying the mutation that causes MEN2. “Years ago, when a person was identified as having thyroid cancer resulting from this syndrome, all members of the family had a dark cloud over their heads. MEN2 is an autosomal dominant disease: the direct descendants of the patient have 50% chance of inheriting it,” he recalls. The closest family members of the person with the disease were then obligated to do frequent ultrasounds and take doses of calcitonin, a hormone secreted by the thyroid that functions like a tumor marker, as its levels increase when the tumor takes root. Today, a genetic test can identify if a patient has a mutation associated with MEN2.

While the type of genetic mutation is a good indicator of the prognosis, this relationship is not a 100% determinant, and individualized assessments should be done for each case. People with the same type of mutation can eventually present different evolutions of the disease. “We found in one family, for example, carriers of the same mutation who present different clinical conditions,” says Maia. In one 17-year-old adolescent, MCT had already manifested itself. But in another member of the family, the tumor was diagnosed later and the patient died at 75 years of age to another cause.

“This multicenter study, despite being more concentrated in the southeastern and southern regions, can be used as a benchmark for the mutations in Brazilian patients with MEN2,” states endocrinologist Denise Engelbrecht Zantut Wittmann, of the Thyroid Cancer Service at the Faculty of Medical Sciences at the University of Campinas (FCM-UNICAMP), who did not participate in the study. For José Augusto Sgarbi, president of the Thyroid Department of the Brazilian Society of Endocrinology and Metabology (SBEM), the results of BrasMEN reinforce the need for the creation of public policies, such as the establishment of a protocol for the genetic testing of patients diagnosed with MCT and close family members. “Today, SBEM recommends that all individuals that have medullary thyroid cancer do the genetic test,” notes Sgarbi. The test is not yet covered by the Unified Health System (SUS).

Whole exome sequencing, Paired-end RNA and genome: New insights about the genetic nature of thyroid cancer at the age of adult and in childhood and applications for clinical practice (nº 14/06570-6) Grant Mechanism Thematic Project; Principal Investigator Janete Maria Cerutti (UNIFESP); Investment R$2,697,516.49.

Scientific article
MACIEL, R.M.B. et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: The BrasMEN study. Endocrine Connections. March 1, 2019.