One day back when Maria Isabel Achatz was a medical student in the late 1990s, she saw a patient with high blood pressure who mentioned in passing that she had had cancer multiple times. That rang some distant bell in Achatz's crowded brain. She went to the library, looked it up (in a book – it was the old days) and thought her patient could have Li-Fraumeni syndrome, a hereditary disorder that causes those who have it to develop multiple different cancers throughout their lifetime.
She told her supervisor her suspicion – and was scolded. Li-Fraumeni is incredibly rare, the senior doctor said: fewer than 200 cases around the world. So what are the odds you found one here in Sao Paulo?
It turns out the odds were higher than anyone ever imagined, but it would be a few more years before Achatz proved that.
She went on to study cancer genetics and got a job at AC Camargo Cancer Centerin Sao Paulo a few years later, where she once again noticed what she thought was Li-Fraumeni – not in one patient this time, but in more than 30 families. Except, she thought, it couldn't be.
A year into her new job, she was presenting data on her clinic at a conference in France when a passerby homed in on the words Li-Fraumeni on her graphs, and began to pepper her with questions. He was a Belgian molecular epidemiologist named Pierre Hainaut who happened to be the world expert on gene mutations that cause cancer.
Maria Isabel Achatz, a cancer geneticist and head of the oncogenetics department at the AC Camargo Cancer Center, in São Paulo, has shown that thousands of Brazilians carry a genetic mutation, once thought extremely rare, that makes them highly vulnerable to cancers.
Victor Moriyama for The Globe and Mail
Together, he and Achatz would go on to do research that found that a mutation in a key cancer-fighting gene, once thought to be incredibly rare, may occur in as many as 300,000 Brazilians. It causes them to get multiple primary cancer tumours – mainly sarcomas, leukemia, breast and brain cancer and adrenal cortical cancer. This is both a massive public-health challenge for Brazil and a dizzyingly rich research opportunity for cancer researchers worldwide.
The gene at the heart of all this is called TP53. It was identified in 1979 and is known by the lofty title of "Guardian of the Genome." Human cells divide continuously as part of growth and maintenance; it happens 10,000 trillion times in the life of an average person. That means our DNA is copied over and over and over – and sometimes, it goes awry. The job of TP53 is to watch for this – and when it sees damage, or a messy copy, in DNA, it freezes the cell. First, it tries for a fix, recruiting other proteins involved in DNA repair. But if that doesn't work, TP53 acts like a poison pill and sends the cell into apoptosis, a sort of scheduled cell death.
People with Li-Fraumeni are born with a mutation of TP53 that means the gene doesn't do its job properly in any cell – and hence, those people are extraordinarily vulnerable to cancer: Achatz has patients who developed tumours in utero and a patient now being treated for a 15th tumour. In 1990, the mutation was pinpointed as the source of Li-Fraumeni syndrome – which until then researchers had speculated might be viral.
"The mutation in the Brazilian population tells us a huge amount about how the gene works and how the mutant form doesn't," David Malkin, director of the cancer genetics program at the Hospital for Sick Children in Toronto, says. (He was one of the researchers who found that inherited mutations in the TP53 gene are the cause of Li-Fraumeni, 25 years ago this week.) Malkin has been collaborating with Achatz since 2008. "If you take 100 cancers out of 100 different people, at least half have a mutation in TP53 – it's an incredibly common messed-up gene in human cancer. And understanding how it behaves in the inherited context – how we can manipulate it there and how other genes interact with it – tells us how TP53 behaves in cancer generally, and can lead to a better understanding of the general population. That's an enormous opportunity."
Hainaut, the Belgian who spotted Achatz's anomalous Li-Fraumeni list, kept a database of TP53 mutations. As the two began to work together analyzing her patients, they realized the one she had found was different from those recorded previously – and that many of her patients had exactly the same mutation, which suggested they shared an ancestor, an uncommon genetic situation known as the "founder effect." Someone – a Caucasian from Spain or Portugal, it seems – brought the gene to Brazil, and had a great many children, and passed it on until it spread through branches of families in the far south and centre of the country.
And that, says Patricia Ashton-Prolla, another Brazilian medical geneticist who works on TP53, is surprising. One would expect the mutation to disappear, since it causes people to have a high risk of having cancer, young – likely before they have children and can pass it on. "Classically, these people are at a higher risk of dying early from cancer," she says.
Andrea Domingues da Silva, left, her mother, Angelina, her uncle Benedito Batista Filho and cousin Rosimeire Domingues all carry a mutation of the TP53 gene that increases their risk of developing multiple cancers. Andrea had three different types of tumours by the time she was a teenager. Now, they and members of their extended family are part of a regular screening and health monitoring program.
Victor Moriyama for The Globe and Mail
But Achatz has found the particular mutation (which goes by the workaday name of R337H) in most of her patients seems to confer roughly a 60-per-cent lifetime risk of cancer compared with the classic Li-Fraumeni risk of 90 per cent. And those who carry a polymorphism, another alteration in the gene, develop cancer 19 years later on average than the rest of patients with Li-Fraumeni but a different TP53 mutation. That meant they lived long enough to pass the syndrome on to children – and in Brazil, where until very recently families were large (Achatz has many in her research cohort with eight, nine or 10 siblings in a generation) and women's ages at first birth was young, that gave the mutation a rare opportunity to spread. And finally, those who had the mutation but survived without cancers seemed to have a selective advantage that caused them to live unusually long and healthily, with far lower incidences of, for example, Alzheimer's and diabetes.
This gave Achatz a vast pool of people to test, as she traced family histories (including tracking down that woman she met first as a medical student).
Four years ago, Andrea Domingues da Silva was referred to Achatz. Then 30, she had had an abdominal tumour at the age of 7, and then one in her kidneys less than a year later – and another in her lungs before she was a teen. Achatz screened her for the mutation and found she had it. Da Silva, in turn, recruited her huge extended family. And in many ways, the geneticist was only telling them something they had suspected, in a way, all along – something was wrong with them.
Da Silva, a pharmacy assistant with large dark eyes and an irrepressible grin, was the first in her generation to have cancer, but the whole family was stalked by the disease. An aunt had leukemia, an uncle had thyroid cancer, another had a brain tumour – and that uncle's grandson died of the same cancer.
She invited Achatz to her home in Turvolandia, a four-hour drive northwest of Sao Paulo, where the doctor did a group genetic counselling session for more than 40 people crammed into a sitting room. She was delivering the unhappy news that they had a 50-per-cent chance of carrying a gene mutation that threatened frighteningly high odds of cancer. But, she urged them, by joining the research, they would have access to extensive medical screening and would be followed for years – and, she was able to tell them, most of the patients in whom they found cancers early were treated with just surgeries, and most avoided chemo or radiation therapy.
Da Silva's cousin, Rosimeire Domingues, 32, is one of the extended family members who signed up to be tested. She has the mutation. But, she says, except for the hospital trips each year, she does her best not to think about it. Her own mother died of a swift-moving leukemia. But, she says, "I'm not worrying about it all the time, being neurotic – if it comes one day, I'll get an operation and take it out. I'm not going to spend time thinking about how I might die one day."
As Achatz's hypothesis that there was comparatively widespread prevalence of Li-Fraumeni in Brazil became more credible and better known, other researchers began to look for the mutation. In Porto Alegre in the south of Brazil, Ashton-Prolla, who works at the Federal University of Rio Grande do Sul, screened women in a preventive breast cancer clinic and found it occurred in one of every 300 of them. That translates to an astonishing 0.3 per cent of the population in the region. In Britain, by way of comparison, Li-Fraumeni is believed to occur in one in 10,000 to one in 25,000 people.
Patients in Achatz's study are monitored using what she dubbed the "Toronto Protocol," based on what Malkin was using at Sick Kids, adapted for Brazil. The tests avoid radiation (no CT scans or X-rays), but every six months each adult patient has a whole-body MRI, ultrasound exams, blood tests and a general exam. (Children are examined every three months.) The cost of those tests, Achatz says, pales in comparison with what it would cost to treat them for multiple cancers.
And the genetic test itself could be performed for just $26 (Canadian) a person, if the health systems were willing to take it on (about 75 per cent of Brazilians use the public health system; some private insurers will now pay for screening if a family member is identified with the mutation). But that, of course, then requires a commitment to pay for the ongoing monitoring of those who have the gene, and that makes everyone nervous, Ashton-Prolla says, since it's uncertain how many patients might be found.
Achatz, who gesticulates with long, thin hands while she does her best to maintain her patience explaining genetics to laypeople, has found herself in the unlikely role of confidante and comforter to a vast extended family – she has introduced branches from one part of the country to those from another – and she roots for them even as she moves on to trying to unlock the next mystery in their genes.
And even as she scans the families in Brazil, she is thinking beyond them. "You cannot say there isn't [a population] like this in another part of the world," she says. "It hasn't been detected – but we haven't looked in every corner."