The subject of the study that was just published in the journal Science Advances has led an extraordinary life. This person developed a tumor as a baby, then others every few years. The patient, who is under the age of 40, has developed and survived twelve tumors, at least five of which are malignant.

Each one has been of a unique kind and has affected a different area of the body. In addition, the person suffers microcephaly, skin patches, and other changes.

“We still don’t understand how this individual could have developed during the embryonic stage, nor could have overcome all these pathologies,” says Marcos Malumbres, director of the Cell Division and Cancer Group at the Spanish National Cancer Research Centre (CNIO).

Malumbres says that the study of this one-of-a-kind case gives us a chance to learn “a way to detect cells with tumour potential well in advance of clinical tests and diagnostic imaging. It also provides a novel way to stimulate the immune response to a cancerous process .”

MAD1L1 mutations in both copies

When the patient first went to the CNIO’s Familial Cancer Clinical Unit, a blood sample was taken to look for changes in the genes that are most often linked to hereditary cancer. However, no changes were found in these genes. Following a comprehensive genomic analysis of the subject, the researchers discovered mutations in the MAD1L1 gene.

The division and proliferation of cells depend on this gene. Researchers at CNIO analyzed the effect of the identified mutations and determined that they alter the number of chromosomes in the cells; all human cells contain 23 pairs of chromosomes.

It has been discovered in animal models that when both copies of this gene—each originating from one parent—have mutations, the embryo dies. To the surprise of the researchers, the person, in this case, had mutations in both copies yet has lived, leading a life that is as typical as one would reasonably anticipate from someone who is unwell.

There has never been another case like this one reported. The study’s co-author, Miguel Urioste, who until his retirement in January of this year oversaw the CNIO’s Familial Cancer Clinical Unit, stated that although “academically we cannot speak of a new syndrome because it is the description of a single case, biologically it is.” 

“Other genes whose mutations alter the number of chromosomes in cells are known, but “this case is different because of the aggressiveness, the percentage of aberrations it produces and the extreme susceptibility to a large number of different tumours.”

How did the tumors vanish?

One of the things that most interested the research team was how easy it was for the patient’s five aggressive cancers to go away. Their opinion is that “the constant production of altered cells has generated a chronic defensive response in the patient against these cells, and that helps the tumours to disappear. We think that boosting the immune response of other patients would help them to halt the tumoural development, ” Malumbres explains.

According to this CNIO researcher, the discovery that the immune system is capable of launching a defensive response against cells with an incorrect number of chromosomes is “one of the most important aspects of this study, which may open up new therapeutic options in the future.” Cells having an aberrant number of chromosomes can be found in 70% of human tumors.

Analysis of a single cell for early diagnosis

Scientists used single-cell analysis technology, which provides a wealth of information that was unimaginable just a few years ago, to study the patient and his or her family members. Several of these people have mutations in the MAD1L1 gene, but only in one copy.

Carolina Villarroya-Beltri, a CNIO researcher and the study’s first author, adds that it requires examining the genes “of each of the blood cells separately. There are many different types of cells in the sample and usually all of them are sequenced, “but by analysing thousands of these cells separately, one by one, we can study what is happening to each specific cell, and what the consequences of these changes are in the patient.”

Among other abnormalities, the single-cell analysis showed that the blood sample included hundreds of chromosomally identical cells, indicating that they were produced by a single, rapidly growing cell. Lymphocytes are protective cells that target particular invaders; on occasion, a lymphocyte, however, multiplies excessively and spreads to become a tumor. In this case, single-cell analysis would be recording the earliest phases of a cancer’s development.

The researchers suggest in their paper that, in light of this discovery, single-cell analysis can be utilized to detect cells with tumor potential well in advance of the development of clinical signs or the detection of analytically detectable indicators.

Researchers Sandra Rodriguez-Perales, head of the CNIO Cytogenetics Unit, Miguel Urioste, head of the CNIO Familial Cancer Clinical Unit until January this year, and Marcos Malumbres, head of the CNIO Cell Division and Cancer Group, served as the study’s coordinators.

Source: 10.1126/sciadv.abq5914

Image Credit: Justin Sullivan/Getty Images


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