A woman survived 12 tumors, at least 5 of them malignant

With inherited gene mutations from both parents, a woman in Spain is battling with 12 tumors in her body.

As stated by the Spanish National Cancer Research Centre (CNIO), the woman first developed a tumor when still a baby and other tumors followed it within five years. 36 year-old-patient has developed twelve tumors, at least five of them malignant in her life. Each one has been of a unique kind and has affected a different area of the body.

"We still don't understand how this individual could have formed 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 claims that research into this particular example reveals "a method to detect cells with cancer potential well in advance of clinical tests and diagnostic imaging. Additionally, it offers a fresh method for triggering an immune response to a malignant process.

MAD1L1 mutations in both copies

A blood sample was taken when the patient first visited the CNIO's Familial Cancer Clinical Unit to sequence the genes most frequently linked to hereditary cancer, but no changes were found in these genes. Following a comprehensive genomic analysis of the subject, the researchers discovered mutations in the MAD1L1 gene.

"No other case like this has ever been described. Academically we cannot speak of a new syndrome because it is the description of a single case, but biologically it is," says Miguel Urioste, who headed the CNIO’s Familial Cancer Clinical Unit until his retirement in January this year.

"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 tumors.”

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The tumors disappeared

One of the details that most intrigued the research team was how quickly the patient's five malignant tumors vanished.

“The constant production of altered cells has generated a chronic defensive response in the patient against these cells, and that helps the tumors to disappear. We think that boosting the immune response of other patients would help them to halt the tumoural development,” explains Malumbres.

Using single cells to provide an early diagnosis

The researchers studied the patient and associated family members using a single-cell analysis technique, which offers a plethora of information that was previously unimaginable. Several of the family members have mutations in the MAD1L1 gene, but only in one of the copies.

It involves analyzing the genes “of 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 analyzing 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,” she also added.

The findings were published in Science Advances on November 2.

Abstract:

Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non–cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility.

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| 11/4/2022