Cesar Martinez’s bone marrow is “on strike.” He does not work. Or not, at least, as it should, explains this 52-year-old man. Due to an inherited genetic mutation, unknown to him until recently, his blood factory has stopped correctly producing red and white blood cells for his body. This halt in the production of blood cells has caused Martinez to develop a myelodysplastic syndrome, a blood cancer that leads him to a bone marrow transplant in the near future. But it’s not all bad news for him. He has just received “a nice surprise”, he says: his eldest son is not a carrier of that genetic alteration that predisposes to these blood diseases; his father and his brother, on the other hand, yes, although for now they are healthy: having the mutation does not necessarily imply developing these ailments, only that there is a greater risk. Martinez’s is one of the more than 100 families that have already gone through the meticulous filter of professionals from the hospital’s Hematological Genetic Counseling Unit, a kind of detective who looks for blood diseases in the family tree of patients with hereditary genetic alterations that increase the risk of this type of pictures.
Genes are the instructions that explain how each cell in the body should function. An alteration or mutation in one of these structures is like “a misspelling” in that manual with the guidelines for life, explains Sara Torres Esquius, genetic adviser at the Vall d’Hebron specialized unit: “It could be that there is a letter change, a piece missing, a page torn out In the end, it is altering this instruction book that tells us how we have to function”, explains the geneticist.
Martinez was detected with a mutation in the DDX41 gene, which can cause the bone marrow to not function properly and not properly produce platelets, red and white blood cells. “He is on strike, he has closed the door,” joked the patient, who had been suffering from intense fatigue for years with no apparent explanation. The medical tests revealed that a genetic defect was making a dent and that strange anemia that appeared in the tests had a reason: he suffered from myelodysplastic syndrome, an unusual blood tumor at his age —it usually appears over 80 years old— and that it ignited all alarms: “After all the studies we discovered that it was hereditary. My parents were tested: my mother was negative and my father, who is 79 years old, positive. My brother, 20 months older than me, is also a carrier,” says Martinez.
There are two copies of each instruction book, one inherited from the mother and the other from the father: if there is an alteration in one of them, the cells can continue to function without problem because there is another complete and correct copy. This is how Torres Esquius explains it to his patients: “Imagine that the bone marrow is a blood factory. She takes the instruction book that she has a misspelling and she doesn’t understand it, but nothing happens because she has another book that is the one she is reading and she is pulling. And to exemplify this we have Cesar’s father: we know that in one of the two copies he has this misspelling, but his core, reading the other copy, goes well. What’s happening? That we get older and there are external factors —such as diet, tobacco, pollution, etc.— [que influyen] and we can acquire mutations. And if of the only copy [entera] of the book, I lose a page, my marrow goes to look for the other and, seeing that it is also wrong, she goes crazy, goes on strike and says: ‘Hey, if they don’t explain it to me fine, I’ll pass’. And this is when we have that myelodysplastic syndrome. In the case of Cesar, one book is damaged because he was born that way and another has been damaged along the way of life”.
Finding those inherited genetic faults that predispose to or explain hematological diseases is the role of the Hematological Genetic Counseling Unit. “What we do is detect a series of mutations in the blood that predispose to the development of haematological and other types of cancer. When we detect the person, this triggers a series of studies also on the family and we do prevention”, explains Julia Montoro, hematologist and head of this specialized unit, a pioneer in Spain. Patients usually arrive derived from other specialists when an alarm signal goes off. For example, when several cases of hematological tumors are discovered in the family, when a cancer appears earlier than usual —like Martinez’s— or when a suspicious combination of various symptoms appears, adds Andres Jerez, a molecular hematologist: “If you have an alteration in the function of the lung added to a hematological cancer makes us suspect that you have a problem with the telomeres [los extremos de los cromosomas]”, exemplified.
Although genetic counseling teams for solid tumors, such as breast cancer, have been around for many years and there are units in different hospitals, knowledge that blood tumors can be inherited is relatively new, and specialized services for detect them, more Hereditary hematological cancer is usually around 10% of all blood tumors, Montoro exposes. A “smaller” percentage, he admits, “but with many implications”: “Detecting mutations is important because we will be able to direct the chemotherapy treatment to avoid unnecessary toxicity and, most importantly, we can better select the donor who will give the bone marrow : if we suspect that this alteration is in the family and the donor is a relative, we must rule out that he also has the mutation because if not, we will be transplanting a diseased bone marrow just like the patient’s”, points out the hematologist.
Being a carrier of a mutation that predisposes to a disease does not mean that one will develop the disease, Montoro insists time and time again. In their unit they always play with two variables: penetrance, which indicates how many of the carriers of the variant will develop the disease, and expressivity, which responds to how sooner or later they will do so and how strong it will be. Each case is different and also depends on the dimension that the investigation of the family tree reaches.
Torres Esquius is already going for the second cousins of Elisabeth Carabante, 40 years old. About twenty relatives of this family have already passed through the consultation of the genetic counselor, who entered the circuit of the unit after an alert from the pediatric service: Alex, Carabante’s youngest son (he is seven years old today), had a count abnormally low platelet count; Coincidentally, like his mother, who also used to have low platelets and remembers, “always, an asterisk in the tests” that the doctors never gave more importance to, he recounts. After the genetic analysis, the Vall d’Hebron team discovered that the little boy, like his mother, carried an alteration in the ETV6 gene, which causes fewer platelets and can cause minor blood problems, bleeding or blood cancer. . Victor, Carabante’s eldest son, does not have the genetic mutation, but Montoro’s team has already detected close to a dozen relatives of this family with the same anomaly. “His case is a very clear example of penetrance and expressivity: the majority have the alteration in ETV6 and have an alteration in platelets, but no one in that family is developing cancer. The penetrance is relatively high, but the expressivity is very variable”, reflects the genetic adviser.
Elisabeth tears up extolling the work of the professionals in the genetic counseling unit and how they gave names and surnames to what was happening to them. Martinez also applauds the answers they have given her and the relief of seeing her son free of that unwanted inheritance. The inspection of the family tree of both families is ongoing, as far as they can go, says Torres Esquius. There is not limit. The more the better. The early detection of these alterations does not serve to prevent future ailments, but it does help to address health problems early, defends Jerez: “There is no preventive intervention, but it can be foreseen, in the sense that you don’t get caught in the moment of the fully open disease, when it has already annoyed you.
The Vall d’Hebron Hematological Genetic Counseling Unit is focused on a paradigmatic case: the story of four brothers with a genetic alteration in common, says Montoro. “The first brother died in the United States 20 years ago: he developed pulmonary fibrosis and some blood problem and died. The second sister, young, developed pulmonary fibrosis and, in the context of a two-lung transplant, she developed anemia and was eventually diagnosed with myelodysplastic syndrome, from which she recently died. And then the alarm goes off: we call the two remaining brothers and it turns out that one was already in a clinical trial at the Hospital de Bellvitge because he had mild pulmonary fibrosis, but there was nothing in his blood; the fourth sister does not have pulmonary fibrosis, but we do a bone marrow study and we see that she has myelodysplasia and now it seems that she is having pulmonary fibrosis ”, says the hematologist. All the brothers suffer from an alteration in the biology of the telomeres due to a mutation in the TERT gene, which is responsible for the maintenance of these chromosome structures. “This is associated with genome-wide instability: if you lose telomeres, you start to repair worse [el ADN] and to have more alterations and mutations”, explains Jerez. The siblings who are still living are now under strict surveillance by pulmonologists and hematologists, while the Hematological Genetic Counseling Unit continues the search for other relatives with the same alteration.
Not everyone wants to know. There are families that refuse to know if they are carriers of a genetic alteration that predisposes to diseases. Understandable, doctors and patients consulted agree. But Torres Esquius only prays that, at least, the decision they make, whatever it may be, be informed: “It is important that, knowing the information about the implications of having this mutation, they decide if they want to be studied and enter a detection program early or not.
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Source: EL PAIS