Pilar García jokingly remembers that her husband tried to blame her for the threat that her children have inside her. Everyone, two boys and one girl, share a hereditary genetic variant which can cause an extremely rare type of tumor. Science proved that the origin of the evil was in her husband, but also that nobody was to blame. The mutation arose by chance does, probably, many decades. Pilar also considers if, had she known that she or her husband was carrying the mutation, she would have had her children. "If I came to know I had not had them," he whispers. "Or yes, because what would we have done without these gems," he says.
Pilar's relationship with her family's illness began in 2004, when her son Juan began to have difficult symptoms to explain: abdominal pains, headaches, high blood pressure … "I did not sleep, I ate like a lime and I was like a lollipop", Pilar account. For years he traveled from doctor to doctor and from hospital to hospital, without accepting the inconclusive answers of the specialists who came to recommend an operation to remove the appendix. "In these cases, conform to the opinion of the doctor that touches you may be a mistake," says Mercedes Robledo, head of the Hereditary Endocrine Cancer Group of the CNIO (National Center for Oncological Research).
It was Robledo's team that in 2008, after the success of an endocrine, managed to identify the source of Juan's suffering and he was able to remove a tumor that had runaway his adrenaline levels. After conducting a genetic study, it was discovered that in addition to the two brothers, the father also carried the same mutation. In his case he had caused a tumor in the neck that could be operated on. More than a decade later, the whole family is fine, although they must follow up annually to intervene in time if the mutated gene generates a tumor again.
These tumors are part of more than 7,000 rare diseases with symptoms that are difficult to identify
Paragangliomas and pheochromocytomas are very rare, almost extravagant tumors, says Alberto Cascón, a member of the same CNIO group. In Spain, little more than twenty cases are detected per year. It is the most heritable tumors. The parents transmit it to their children in up to 40% of the cases and in the CNIO they know families with up to 10 affected members. In many cases, in addition to the risk of metastasis, which occurs in 20% of cases, patients have very poor quality of life. Causes imbalances in the body that can cause the need to go to the bathroom 40 times a day.
As in the case of Pilar, families with these tumors must first overcome ignorance. There are more than 7,000 rare diseases with symptoms and causes that a doctor may never have seen or studied. This dispersed knowledge could be improved, according to Robledo, by centralizing the cases or through specialized centers such as the Rare Diseases Network Biomedical Research Center (CIBERER), which brings together specialists in infrequent ailments.
Given its hereditary nature, once patients have identified that they have one of these tumors, the next step is to identify the specific mutation that caused it and to test other family members so that, if they carry it, they can be included in the programs of prevention, early detection and monitoring. However, as the CNIO researchers comment, not all family members want to know. "Some prefer not to be tested," says Cascón.
For those who do want to know, the group led by Robledo has accumulated a record of 800 index patients (between families and individual cases) since 1996 and receives samples for genetic diagnosis from Spain and other countries such as Germany, Italy or Canada. In some cases, the discovery of a new mutation can explain the illness of a person and his family in one country and another in a different one, but little by little accumulates information that can be incorporated into the panels of genetic diagnosis for the early detection of the disease.
For now, the only approved treatment for this type of tumor is surgery. Being such rare diseases, it is difficult to consider the development of specific drugs for them, but patients could benefit from the reuse of effective medications for other diseases. "We want to develop technologies that can be applied easily in hospitals and as soon as possible," says Robledo. On the other hand, "a fundamental part of our work is to keep all of your clinical data up-to-date, in order to know if the fact of being a carrier of a mutation in the new genes also implies an increase in the risk of developing other tumors," he adds.
Despite her years of pilgrimage in search of an explanation of the evil her son suffered, Pilar considers herself lucky, for having found the team of Robledo and Cascón and because although all her children and her husband have the threatening mutation, they are still healthy and with life. Some stories are not so happy and there are families diminished by these strange tumors. Scientists work so that, albeit very slowly, they become less and less.
Half of these tumors are caused by mutations in genes involved in the Krebs cycle, essential in the respiration of cells and in how they obtain energy. With this knowledge, a CNIO team has sequenced all the genes involved in this cycle in search of unknown causes of these types of cancer. The group, led by Alberto Cascón and with Laura Remacha as the first signatory, has just published in the magazine American Journal of Human Genetics the finding that the DLST gene affects the development of this disease when it is mutated. The gene is already included in the genetic diagnostic panel for early detection of the disease.