Million-dollar project against familial cancer wants to rescue thousands from ‘genetic purgatory’ | Health and wellness

“Fear is not the right word to describe what I feel,” explains Carlos Rospide, “but there is anxiety. You’re always waiting for something. You hope it doesn’t happen, but you know it could happen.” At the age of 60, two months before retirement, Rospide was diagnosed with breast cancer. This was the first of the bad news that piled up. Soon after, he was diagnosed with kidney cancer and then another prostate cancer. Meanwhile, three of his five brothers received similar messages: one of them was being treated for an appendix tumor, another also developed prostate cancer, and his sister was diagnosed with breast cancer.

This pattern was clearly consistent with familial cancer, but routine genetic testing was inconclusive. Only a minimally suspicious change was found in the DNA of one of the genes studied. At the time, the variant was classified as “uncertain significance”, but over time its liability has been largely eliminated. The situation means that they, like many other families in similar circumstances, find themselves in a limbo of knowledge and information. They know something abnormal is happening, but they don’t know what is causing the change or who is carrying it in their DNA. Today is World Cancer Day.

Now a project involving nine Spanish research centers and funded with more than three million euros by the Precision Medicine Infrastructure of the Carlos III Health Institute is looking for the cause in some 300 families in this situation. To do this, they will study not only the most common genes, but also all DNA; They will use computer tools to filter the avalanche of information and conduct special laboratory experiments for each potential change. Carlos Rospide’s family is one of these 300 families.

“The National Health System offers a genetic diagnosis to families who clearly have hereditary cancer, but many remain unsolved,” explains Mercedes Robledo, director of the Hereditary Endocrine Cancer Group of the CNIO, a center that is involved in the project with four groups. , called IMPaCT-VUScan. “Now we want to go well beyond the diagnostic procedure to help some of them, but also to develop tools that will help the doctor make decisions in the future,” says Robledo.

family component

It is believed that “between 10% and 15% of tumors have a familial or hereditary component,” explains Maria Kurras, head of the familial cancer unit at the CNIO, who, in addition to participating in the project, takes care of the Rospide family. . This component may be suspected when more cases than usual accumulate in one family, if tumors develop in different organs, or if they appear at a very early age. Although tailored care and follow-up can reduce mortality, in many cases the exact cause is not known.

For example, in the case of breast cancer, “known susceptibility genes only explain 30% to 40% of cases with hereditary influence,” Kurras explains. Suspicion does not necessarily imply a family connection, but “in general, if all suspected cases are taken into account, in more than 80% of cases the responsible mutation is not found,” admits Consi Lazaro, head of the research group at the journal Hereditary Cancer. from the Catalan Institute of Oncology IDIBELL and project leader of IMPaCT-VUScan.

In addition, tests are increasingly showing variants of undetermined significance, changes in DNA for which there is not enough information to know whether they are responsible for the risk. Exactly what happened in the original diagnosis of the Rospide family, with the added predisposition that the variant in question was represented by four brothers, all of whom developed a tumor; and that the only brother who was not harmed did not inherit it.

While the vast majority of these undefined variants ultimately turn out to be benign (they cause harmless changes) and not associated with cancer, they are a “geneticist’s nightmare,” Robledo says. The criterion is that no clinical decisions should be made based on their presence, but they increase uncertainty and are said to place the host in “genetic purgatory” beyond uncertainty. Kurras stresses the importance of how these results are communicated, and while reactions vary, he admits they usually interpret it “as something bad.” They feel that something strange has been discovered that they don’t know what to tell me about, and they end up feeling the same or even worse than they were.”

The occurrence of this type of change increases as testing increases and genetic data becomes available. In Spain, the likelihood of their occurrence varies depending on the autonomous community, since “there is great inequality between them,” Lazaro admits. “While some sequence a panel of ten genes, others look at more than a hundred genes (the vast majority of which are associated with increased cancer risk),” he explains. A paradox arises: the more data requested, the greater the likelihood of obtaining an answer, but also the greater the likelihood of uncertainty. It was as if repentance was also included in prayer.

The same thing will happen in the IMPaCT-VUScan project, in which the translation of your display surname will be something like “study of variants of undetermined meaning.” If you sequence the entire genome, “there will be a lot of them,” Lazaro admits. But unlike clinical practice, in this case they will be prioritized and carefully studied in order to come to some conclusion. “I volunteered to seek knowledge and help solve the problem of familial cancer and improve survival,” explains Rospide. “It’s a slow process though,” he admits almost immediately.

Project on the path to justice

The vast majority of changes you find in families’ DNA will be harmless and more or less common. To filter and prioritize all this noise, they have developed bioinformatics tools that take into account how these gene variants affect the proteins they give rise to, how they change their shape in space, the place they occupy in denser environments. cellular network or how evolution preserved them. In doing so, they will select specific candidates in each family and design in the lab “completely customized experiments for each of the variants that will allow us to know whether they actually have an effect,” Robledo explains.

The resulting information “will feed back into the bioinformatics tools to feed back the real data to the artificial intelligence and what the forecast told us,” the researcher continues, setting an ambitious but challenging goal: it will help make decisions in the future. directly in a medical consultation. Because not only are these experiments generally not available in everyday clinical practice, but “they can take years and may not even succeed,” suggests Robledo, for whom this project is “quite unique and innovative due to the level of resources, instruments and research planned.” . “. For Lázaro, there is another thing that makes this important, and that is that “it enabled the creation of a network, the criteria were unified and was the driving force for presenting a single portfolio of services for the entire NHS.” System. This portfolio will ensure equity across regions in diagnostic tests for familial cancer.”

The value of information

Rospide admits that this situation “completely changes the structure of life. When you are healthy or think you are healthy, life goes by without paying much attention to time. With this approach, the perspective changes and becomes more short-term, the distance of concern becomes shorter: the next visit, the next test. It makes me laugh when the news says that someone has beaten cancer. You’ll get over it when they stop checking on you.” Although no mutation has been found to explain the cancer in the Rospide family, all siblings must follow a schedule of visits and medical examinations tailored to their situation – a regimen certainly more extensive than what is usually recommended. However, knowledge of the exact changes does not necessarily have to be associated with other treatment.

There are clinical trials of some preventative treatments for familial cancer, but none are approved as such (with the exception of prophylactic surgery in some cases of breast cancer predisposition). Yes, there are special drugs for treating tumors with mutations in the BRCA1 and 2 genes (most common in familial breast cancer) or for patients with colon cancer and changes that make them more sensitive to immunotherapy, but it is normal that the mutation does not dictates treatment. “Identifying new responsible variants could lead to the use or development of new drugs, even in people in whom these changes occur in isolation and in unfamiliar ways,” Lazaro explains, “but this will be difficult, among other reasons, because the proportion of patients for each it won’t be enough for them.”

What purpose could there be in knowing the responsible mutation? On the one hand, it eliminates the increased risk among those people in the family where it does not exist, relieving their anxiety. This also includes sons and daughters, which is a major concern in these situations, as well as the ability to offer genetic counseling if they choose to receive it. On the other hand, to adjust and personalize care and diagnosis. This is what, for example, a multi-year study conducted by Robledo’s group in three families with a high risk of pheochromocytoma, a rare tumor of the adrenal gland, revealed. They determined that the cause in these three cases was a gene never previously linked to the disease, they shared it with an international consortium and found other families with the same changes. This allowed them to conclude that “they had a specific clinic,” Robledo explains. “They had a higher risk of metastasis, so closer surveillance was desirable, and they tended to appear in certain locations, so now we know where to look.”

Faced with the uncertainty they find themselves in, “this information gives these families the answer to one of their questions: why did this happen to me,” Lazaro emphasizes. “It’s also a tool that allows them to empower themselves in the face of many life-altering decisions and tailor the care they receive, which is, after all, what we’re talking about when we talk about personalized medicine. It gives them control over some aspects of their lives.” “I’m not looking for any role,” says Rospide. “If I tell my story, it’s because I think it can help.”

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