It all started at the age of two with the diagnosis of embryonic cancer. Then, at 15, enchondromatosis and cervical carcinoma. And so up to 12 tumors.
At 20 years of age, a pleomorphic adenoma in the parotid gland; at 21, a spindle cell sarcoma; at 24, multinodular goiter; between the ages of 20 and 24 several dysplastic nevi, a lipoma and a pilomatrixoma, and between the ages of 20 and 28 several adenomas and adenocarcinomas in colon and rectum. So far, at 36 years old, he has no active tumor.
His exceptional life is the subject of a study published in the journal “Science Advances”. In less than forty years, the patient has developed twelve tumors, at least five of them malignant. Each one has been of a different type and in a different part of the body. In addition, she has spots on the skin, microcephaly and other alterations.
“We still don’t understand how it could have developed during the embryonic stage, nor how it could have overcome all these pathologies,” acknowledges researcher Marcos Malumbres, from the National Cancer Research Center (CNIO).
For Malumbres, the fact that the five aggressive cancers developed by the patient disappeared relatively easily is particularly striking. The hypothesis is that “the constant production of altered cells has generated a chronic defensive response against these cells, and this helps tumors to disappear. We think that boosting the immune response of other patients would help them slow down tumor development.”
In any case, acknowledge ABC Health Carolina Villarroya-Beltrifirst author of the study, “the fact that this person survived embryonic development and reached the age of 36 remains puzzling and we do not have an explanation.”
Put to explain it, Villarroya considers that the fact that the resolution of the tumors has been favorable in all cases may be thanks to the combination of several effects. In the first place, “the genomic instability caused by its mutations initially makes it more predisposed to developing cancer, but in the long term it could make these tumors accumulate too many mutations and could not finish developing as effectively.
Second, he continues, “the constant activation of the immune system that we observed, specifically the expansion of a subtype of non-canonical T cells, gamma-delta, may have contributed very significantly to the elimination of these tumors.” And, finally, “we also observed that some mitochondrial proteins, called humanins, are induced, and that it has been seen that they improve cell viability in different contexts, and the importance that they may have in this type of case is an attractive hypothesis for Keep studying”.
For Malumbres, the discovery that the immune system is capable of triggering a defensive response against cells with the wrong number of chromosomes is “one of the most important aspects of this study”.
Then, Can the immune system be trained? Villarroya points out that “the study of the special characteristics of this person’s immune system can give us a lot of information about new ways of approaching cancer immunotherapy, such as the role that gamma-delta T cells may have.”
When the patient came to the CNIO Family Cancer Clinical Unit for the first time, a blood sample was taken to sequence the genes most frequently involved in hereditary cancer, but it was not detected no alteration in them.
Their entire genome was then analyzed and mutations in a gene called MAD1L were detected. This gene is essential in the process of cell division and proliferation.
Academically we cannot speak of a new syndrome because it is the description of a single case, but biologically it is.
The researchers analyzed the effect of the detected mutations and concluded that they cause changes in the number of chromosomes in cells: all cells in the human body have 23 pairs of chromosomes.
In animal models, when there are mutations in both copies of this gene, each coming from a parent, the embryo dies. But, to the astonishment of the researchers, the person in this case has mutations in both copies and has survived, living as normal a life as can be expected from someone in poor health.
No case like this has ever been described.
According to the then director of the CNIO Family Cancer Clinical Unit and author of the study, Miguel Urioste, “academically we cannot speak of a new syndrome because it is the description of a single case, but biologically it is.”
“It can be considered a new type of Mosaic Variegated Aneuploidy Syndrome (MVA)with an unprecedented tumor susceptibility for this type of syndrome”, adds Villarroya.
To study the patient and related family members, several of whom have mutations in the MAD1L1 gene, but only in one of the copies, single-cell analysis technology was used.
It involves analyzing the genes “of each of the blood cells separately,” explains Villarroya. By analyzing thousands of these cells separately, it is possible to study what happens to each specific cell and what are the consequences of these changes.
Thus, single-cell analysis revealed, among other anomalies, that the blood sample contained several hundred chromosomally identical lymphocytes, thus coming from a single rapidly proliferating cell.
The lymphocytes are defensive cells that attack specific invaders; sometimes, however, a lymphocyte grows too large and spreads to form a tumor. That is the process that the single-cell analysis would be capturing in this work: the first stages of cancer.
According to Malumbres, the study opens «a way to detect cells with tumor potential long before clinical trials and diagnostic imaging, in addition to a novel way of stimulating the immune response against a cancerous process”.