A million-dollar project against family cancer wants to get thousands of people out of “genetic purgatory”

“Fear is not the word to describe what I feel,” explains Carlos Róspide, “but there is a concern.

You always expect something.

You hope it doesn't happen, but you know it can happen.”

At the age of 60, two months before retiring, Róspide was diagnosed with breast cancer.

That was the first of the bad news that was accumulating.

Shortly afterward he was diagnosed with kidney cancer, and then another prostate cancer.

Meanwhile, three of his five brothers received similar messages: one of them was treated for a tumor in his appendix, another also developed prostate cancer, and his sister had breast cancer.

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The pattern clearly responded to a familial cancer, but routine genetic testing was inconclusive.

Only a minimally suspicious change was detected in the DNA of one of the genes studied.

This variation was classified at the time as “of uncertain significance”, but over time it has practically been ruled out that it is responsible.

The situation means that they find themselves, like many other families in these circumstances, in a limbo of knowledge and information.

They know that something abnormal is happening, but it is not known what alteration it is due to or who carries it in their DNA.

Today is World Cancer Day.

Now, a project in which nine Spanish research centers participate and financed 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 not only study the most common genes, but all the DNA;

They will use computer tools to filter the avalanche of information and will develop specific laboratory experiments for each candidate alteration. Carlos Róspide's is one of those 300 families.

“The National Health System offers a genetic diagnosis to families who clearly have a hereditary cancer pattern, but many remain unresolved,” explains Mercedes Robledo, director of the CNIO's Hereditary Endocrine Cancer Group, a center that participates with four groups. in the project, called IMPaCT-VUScan.

“Now we want to go far beyond the diagnostic routine to help some of them, but also to develop tools that help the doctor's decision-making in the future,” says Robledo.

family component

It is considered that “between 10% and 15% of tumors have a familial or hereditary component,” explains María Currás, head of the Family Cancer Unit at the CNIO and who, in addition to participating in the project, cares for the Rospide family.

This component may be suspected when more cases than usual accumulate in the same family, if tumors develop in different organs or if they appear at a very early age.

Although adapted care and follow-up manage to reduce mortality, in many cases the cause that causes them is not known with certainty.

In the case of breast cancer, for example, “the known predisposition genes only explain between 30% and 40% of cases with hereditary influence,” explains Currás.

Suspicion does not necessarily imply a family pattern, but “overall, if all suspected cases are taken into account, in more than 80% of cases the responsible mutation is not found,” acknowledges Conxi Lázaro, head of the research group. in Hereditary Cancer from the Catalan Institute of Oncology-IDIBELL and leader of the IMPaCT-VUScan project.

In addition, variants of uncertain significance appear more and more frequently in tests, changes in DNA for which there is not enough information to know whether they are responsible for the risk.

Precisely what happened in the initial diagnosis of the Róspide family, with the added predisposition that the variant in question was presented by four of the brothers and all of them had developed a tumor;

and that the only brother who had not suffered any had not inherited it.

María Currás, head of the CNIO Family Cancer Clinical Unit. Laura M. Lombardía/ CNIO

Although the vast majority of these uncertain variants end up being benign (they produce a harmless change) unrelated to cancer, they represent “a nightmare for geneticists,” says Robledo.

The criterion is that no clinical decision should be made based on their presence, but they multiply uncertainty and it has been said that, beyond limbo, they place the carrier in a “genetic purgatory.”

Currás emphasizes the importance of how these results are communicated, and although the reactions are variable, he recognizes that they usually interpret it “as something bad.

They perceive that something strange has been found, something about which they do not know what to tell me and in the end they feel the same or worse than they were.”

The appearance of this type of changes is increasing, as the extent of testing and genetic data received increases.

In Spain, the probability of them appearing varies depending on the autonomous community, because “there is great inequality between them,” Lázaro acknowledges.

“While some sequence a panel of ten genes, others study more than a hundred [the vast majority of those that have been linked to an increased risk of cancer],” he explains.

He sees the paradox that the more data requested, the more likely it is to obtain an answer, but also the more likely it is that uncertainties will appear.

As if penance were also included in prayer.

That is what will also happen in the IMPaCT-VUScan project, in which the translation of your displayed surname would be something like “exploring variants of uncertain meaning.”

By sequencing the entire genome, “lots of them will appear,” Lázaro acknowledges.

But unlike in clinical routine, in this case they will be prioritized and studied in depth, seeking to reach a conclusion.

“I volunteered to seek knowledge and to help tackle the problem of family cancer and improve survival,” explains Róspide.

“Although it is a slow process,” he admits almost instantly.

A project towards equity

The vast majority of the changes that you will find in the DNA of families will be harmless and more or less common.

To filter and prioritize among all that noise, they have designed bioinformatics tools that take into account how these variants in the genes affect the proteins to which they give rise, how they change their shape in space, the place they occupy in the more than dense cellular network or how evolution has conserved them.

With all this, they will choose specific candidates in each family and develop in the laboratory “absolutely individualized experiments for each of the variants, which will allow us to know if they really have an effect,” explains Robledo.

Conxi Lázaro, head of the Hereditary Cancer research group at the Catalan Institute of Oncology-IDIBELL and leader of the IMPaCT-VUScan project.

/ Raquelgraficraquelgrafic (Idibell)

The information obtained “will return again to the bioinformatics tools, to feed real data to the artificial intelligence and what the prediction had told us,” continues the researcher, with the ambitious but complex objective that, in the future, it will help make decisions directly in the medical consultation.

Because these experiments are not only usually unavailable in clinical routine, but “they can take years and even not be successful,” assumes Robledo, for whom this project is “quite unique and pioneering due to the level of resources, tools and studies planned.” .

For Lázaro there is another thing that makes it important, and that is that it “has allowed the creation of a network, unified criteria and has served as a driver for the presentation of a unified portfolio of services for the entire National Health System.

This portfolio will guarantee equity between regions in diagnostic tests for familial cancer.”

The value of the information

Róspide recognizes that a situation like his “completely changes the structure of life.

When you are healthy, or think you are, life goes by without paying much attention to time.

With something like this, the perspective changes and becomes more short-term, the distance of worries becomes shorter: the next visit, the next test.

It makes me laugh when it says in the news that someone has overcome cancer.

You get over it when they stop testing you.”

Although no mutation has been found to explain the Rospide family's cancer, all siblings must follow a schedule of visits and medical examinations tailored to their situation, a regimen undoubtedly more extensive than that usually recommended.

Knowing the precise change, however, does not have to be linked to a different treatment.

There are clinical trials with some preventive therapies against familial cancer, but none are approved as such (except for preventive surgery for some cases of predisposition to breast cancer).

Yes, there are specific drugs to treat tumors with mutations in the BRCA1 and 2 genes (precisely the most common in familial breast cancer) or for patients with colon cancer and changes that make them more sensitive to immunotherapy, but the normal thing is that the mutation does not dictate the treatment.

“Identifying new responsible variants could serve to use or develop new drugs, even in people where these changes occur in an isolated and unfamiliar way,” explains Lázaro, “but it will be difficult, among other things because the proportion of patients for each of them It will be small.”

What purpose can it be to know the responsible mutation?

On the one hand, to rule out an increased risk in those people in the family where it is not present, relieving their anxiety.

This also includes sons and daughters, a primary concern in these situations, in addition to the possibility of offering genetic counseling if they decide to have one.

On the other hand, to adjust and personalize care and diagnoses.

This is what allowed, for example, a multi-year investigation carried out by Robledo's group in three families with a high risk of pheochromocytoma, a rare tumor of the adrenal glands.

They identified that the cause in those three cases was in a gene never before related to the disease, they shared it with an international consortium and located other families with the same changes.

That allowed them to deduce that “they had a specific clinic,” explains Robledo.

“They had a higher risk of metastases, so closer monitoring was advisable, and these tended to appear in certain places, so now we know where to look.”

Faced with the limbo in which they find themselves, “the information gives these families an answer to one of their questions: why did it happen to me,” highlights Lázaro.

“In addition, it is a tool that allows them to empower themselves in the face of many vital decisions and adjust the care they receive, which after all is what we talk about when we talk about personalized medicine.

It gives them the power to control some aspects of their life.”

“I'm not looking for any role,” says Róspide.

“If I tell my story, it is because I think it can help.”

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