The exceptional case of a patient who has survived 12 tumours will help improve cancer diagnosis.

Nov 6, 2022 | Current affairs, Featured, Post, Revista Lloseta, Thursday Daily Bulletin, Tradition, Uncategorized

The CNIO team has discovered that a woman’s immune system naturally generates a strong anti-inflammatory response that fights tumours; understanding how it achieves this will help stimulate the immune system in other cases, say the researchers.

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This week’s study in Science Advances describes an exceptional case: the case of a Spanish patient who suffered and overcame 12 tumours. She had her first tumour process when she was almost a baby, and then others every few years in her forties.

Of those 12 tumours, at least five were malignant. Each one is in a different part of the body; each one of a different type. She also has skin spots, microcephaly and other alterations. According to Marcos Malumbres, head of the Cell Division and Cancer group at the Spanish National Cancer Research Centre (CNIO), “we still don’t understand how she was able to develop during her embryonic stage, nor how she was able to overcome all these pathologies”.

The study of this unique case opens up, according to Malumbres, “a way to detect cells with tumour potential well in advance of clinical tests and diagnostic imaging; and also a novel way to stimulate the immune response to a cancerous process”.

Mutations in both copies of the MAD1L1 gene
When the patient first came to the CNIO Family Cancer Clinical Unit, a blood sample was taken to sequence the genes most frequently involved in hereditary cancer, but no alteration was detected in them. The researchers then analysed their entire genome, and found mutations in a gene, called MAD1L1.

This gene is essential in the process of cell division and proliferation. The CNIO researchers analysed the effect of the mutations detected, and concluded that they cause alterations in the number of chromosomes in the cells – all cells in the human body have 23 pairs of chromosomes.

The researchers found that the 12 tumours, five of them malignant, were caused by the patient inheriting mutations in a gene essential for life from both parents.

In animal models, it has been observed that when there are mutations in both copies of this gene – each from one parent – the embryo dies. To the astonishment of scientists, the person, in this case, has both copies mutated and has survived, living as normal a life as his delicate health allows.

No other case like this has ever been described. According to the co-author of the study, Miguel Urioste, who headed the CNIO’s Familial Cancer Clinical Unit until his retirement in January this year, “academically we cannot speak of a new syndrome because it is the description of a single case, but biologically it is”.

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

Why did the tumours disappear?
One of the facts that most intrigued the research team was that the five aggressive cancers developed disappeared relatively easily. Their hypothesis 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 disappear. We think this could be useful for other patients: boosting their immune response would help them to stop tumour development,” explains Malumbres.

The discovery that the immune system is capable of unleashing a defensive response against cells with the wrong number of chromosomes is, according to this CNIO researcher, “one of the most important aspects of this study, which may open up new therapeutic options in the future”. Seventy per cent of human tumours have cells with an abnormal number of chromosomes.

Single-cell analysis for early diagnosis
To study the patient and his relatives – several with mutations in the MAD1L1 gene, but only in one of the copies – the scientists used single-cell analysis technology, which provides a wealth of information that was unthinkable just a few years ago.

It involves analysing the genes “in each of the blood cells separately,” explains Carolina Villarroya-Beltri, CNIO researcher and first author of the study. 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 are the consequences of these changes in the patient”.

Single-cell analysis revealed, among other abnormalities, that the blood sample contained several hundred chromosomally identical lymphocytes, thus coming from a single, rapidly proliferating cell. Lymphocytes are defensive cells that attack specific invaders; sometimes, however, a lymphocyte proliferates too much and spreads to form a tumour. That is the process that the analysis of single cells – the earliest stages of cancer – would be capturing in this work.

Based on this finding, the researchers propose in their paper that single-cell analysis can be used to identify cells with tumour potential long before clinical symptoms, or markers observable in analytical tests, appear.

The study was coordinated by researchers Sandra Rodríguez-Perales, head of the CNIO Cytogenetics Unit; Marcos Malumbres, head of the CNIO Cell Division and Cancer Group; and Miguel Urioste, head of the CNIO Family Cancer Clinical Unit until January this year.

This study has been funded by the Ministry of Science and Innovation; the Scientific Foundation of the Spanish Association Against Cancer; and the Community of Madrid.