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María Isabel Achatz was still finishing her medical studies in Sao Paulo, Brazil, at the end of the 1990s when she met a patient who would change forever not only her career, but also her life.
It was a woman who had been diagnosed with cancer six times , all primary tumors, with no apparent relationship to each other.
Achatz then suspected that it was a manifestation of the Li-Fraumeni syndrome, a genetic predisposition that promotes a wide range of cancers in the same family.
“I spoke with my supervisors and they mentioned that (at that time) there were only 200 cases of this disease in the world,” the doctor tells the BBC in Portuguese.
The case was not resolved at the end, but years later the suspicion led Achatz to discover a genetic mutation that revealed that the existence of the Li-Fraumeni syndrome in the southern and southeastern regions of Brazil was greater than anywhere else in the world. world.
He was also able to trace cases of different families in several cities that had a common ancestor: a muleteer who lived in the eighteenth century .
“Guardian of the genome”
The Li-Fraumeni syndrome is triggered by a mutation in a gene called TP53, which doctors consider a kind of “guardian” of our genome .
“When the cells divide and there is an error, the body needs to correct the error so that the cell does not remain altered or to kill it.Cancer occurs when the body can not do that and damaged cells proliferate,” explains Maria Nirvana Formiga, coordinator of the Department of Oncogenetics of the CA Camargo Cancer Center in Sao Paulo.
It was in the same hospital where Achatz diagnosed at least 35 patients with the syndrome in their first year working there.
“They told me I was crazy, but I saw that something different was happening, ” she says.
TP53 performs several tasks during the cell cycle and one of them prevents abnormal cells from proliferating and generating tumors.
A mutation in this gene compromises this function and, if the mother or father has it, it is enough for it to pass to the next generation.
“Basically, a person with Li-Fraumeni has a much higher chance of developing cancer in certain parts of the body compared to the general population,” explains Formiga.
A carrier of the mutation may have a tumor or even several, such as the first Achatz patient, or never develop the disease.
However, it is very common to have a history of several family members killed by tumors.
The most common cases are breast cancer before age 35, sarcomas (rare cancers that develop in muscles, bones, nerves, cartilages, tendons, blood vessels and fatty and fibrous tissues) before age 45, as well as leukemia or malignant tumors in the central nervous system.
“When there are relatives with different tumors, we consider the possibility of Li-Fraumeni in that family,” explains the researcher.
In the 2000s, Achatz’s research caught the attention of a French colleague who encouraged her to investigate the ” unique situation ” observed in her patients.
At that time, doctors in other regions of Brazil had also recorded frequent diagnoses of the syndrome.
Achatz began by analyzing the TP53 gene in people who he suspected were carrying Li-Fraumeni.
The geneticist discovered that the mutation occurred in a different part of the gene, which made the Brazilian cases of Li-Fraumeni unique in the world.
He then asked his patients to ask their relatives if they were interested in knowing if they were also carrying the mutation.
This is how nutritionist Regina Romano discovered why her family lost so many members because of cancer.
“One of my grandmother’s nieces was a patient of Dr. Achatz and she got in touch with the other relatives,” she says.
At the first meeting with the family, the doctor had an audience of no less than 30 relatives who heard an explanation about Li-Fraumeni and why she needed to collect blood samples from all those interested in having a genetic test.
Tests showed that the family matriarch had the defective gene, even though she did not develop the disease, and that three of her four children also had it and transmitted it to their descendants.
“Then she told me: ‘This is due to my grandfather, a muleteer, he used to disappear for six months and I think he left some families on the road.’ That caught my attention,” recalls Achatz.
During the 18th century, the muleteers drove horses and mules through the south of Brazil, selling all kinds of merchandise.
The geneticist investigated maps of the most common routes and cross-referenced the data with the location of the patients who were diagnosed with Li-Fraumeni.
The two maps, he says, “were identical.”
Achatz and his colleagues decided to investigate the origin of the mutation.
With genetic material from the patients, the researchers compared specific characteristics that only people in the same family would present and that function as a kind of paternity test.
“In nine families we find the same profile and the probability of that happening in the general population is almost impossible,” Achatz reports.
“It became clear that they had a common origin, so we made a historical hypothesis.”
The special mutation of the TP53 gene gives the Li-Fraumeni cases in Brazil different characteristics compared to other parts of the world, one of them is the probability of developing tumors.
In general, people who have that gene in the world have between 90 to 100% more likely to have cancer than the normal population.
In Brazil, however, women are 78% more likely and among men it is less than 50%.
In the rest of the world, genetic mutations in TP53 often cause early cases of cancer: in 50% of cases, it occurs before the age of 30. In Brazil, the probability is 30%.
“The Brazilian gene carriers live longer and are more likely to have children and transmit the mutation,” explains Achatz.
That is behind the higher prevalence of the disease in the south and southeast of Brazil: studies in two cities (Porto Alegre and Curitiba) showed that 1 in every 300 people has Li-Fraumeni. Around the world, rates are estimated between 1 in 5,000 and 1 in 20,000 people.
Great family reunions
The need for constant medical monitoring and the common origin of the disease led to greater interaction between the families affected by Li-Fraumeni, including Facebook groups that connected relatives who previously did not know each other.
“The hospital has become my second home and I meet relatives from other states there, and we try to schedule our medical exams at the same time,” explains Vania Nascimento.
His grandparents had 10 children and eight died of cancer. In the larger family, at least 20 people had the disease.
Vania was the first of the family to survive.
“Every time one of us died, we wondered who would be next, we never understood why there were so many cases.”