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Exceptional cancer case offers new hope for diagnosis and treatment

Researchers at the Spanish National Cancer Research Centre (CNIO) have described the exceptional case of a 36-year-old woman who has survived 12 tumours in her life so far. The paper, published in Science Advances, details the unique genetic mutations carried by the patient and suggests that her unique case could open up new possibilities for diagnosis and treatment of many different types of cancer.

A difficult start in life

When researchers at the CNIO first came across this particular patient, they were understandably shocked to discover the complex medical history of this individual. Starting when they were still an infant, this individual had developed 12 tumours (5 of which were malignant) in under 40 years. And each of these cancers had developed in a different part of the body.

To have survived this long was remarkable, but the picture would only get more complicated when the researchers looked at their genetics. Initially, the CNIO team took a simple blood test and searched for the genes most frequently involved in hereditary cancer – they found nothing. They then sequenced the individual’s entire genome and found mutations in the MAD1L1 gene that is associated with cell division and proliferation.

Further analysis showed that these mutations were causing changes in the number of chromosomes present in certain cells, a feature seen in other known disorders. So why is this case so unique? In mice, mutations in both alleles of the MAD1L1 gene causes the embryo to die. This is the first known case where a human has exhibited mutations in both copies of the gene and survived. What’s more, the individual does not seem to have the learning difficulties seen in patients with mutations in just one copy of the gene.

“We still don’t understand how this individual could have developed during the embryonic stage, nor could have overcome all these pathologies,” said Marcos Malumbres, head of the Cell Division and Cancer Group at CNIO.

A disappearing act

The mere fact this individual managed to survive into adulthood is astonishing in itself, but the researchers were particularly intrigued by their body’s ability to fight cancer – their tumours seemed to disappear relatively easily. To investigate this further, they employed single-cell transcriptomics to study the molecular consequences of germline chromosomal instability.

Figure 1: Transcriptomic analysis of peripheral blood cells with biallelic MAD1L1 mutations.
(A) Uniform manifold approximation and projection (UMAP) of cells from the indicated samples. (B) UMAP distribution of cell types. DC, dendritic cell; Treg, regulatory T cell. ASDC, AXL(+) dendritic cells; TCM, Central memory T cells; TEM, T effector memory; HSPC, Hematopoietic stem and progenitor cells; ILC, Innate lymphoid cells; MAIT, Mucosal-associated invariant T cells. (C) Percentage of L1 cell types in the indicated samples. (D) Number of cells in the specific cell types included in the L1 “other T” classification showing an overrepresentation of γδ T cells in the proband. (E) Expression of specific markers of γδ T cells and B cells expressing the κ chain. (F) List and scores (Wilcoxon rank sum test) of the top up-regulated genes in proband versus control PBMCs. (G) Aggregated expression of the set of top genes up-regulated in proband cells in the different individuals analyzed. (H) Relative levels of a panel of cytokines in the plasma of controls and the proband. (I) Top ligand-receptor interaction pairs overrepresented in the proband compared to the controls.

They found defects in translation and ribosome biogenesis and activation of interferon and NFκB signalling. The single-cell results also suggested that a non-cell autonomous inflammatory response to aneuploidy helps the individual fight cancers – potentially due to increased levels of specific cytokines and inflammatory molecules in the blood plasma.

“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,” explains Malumbres. “We think that boosting the immune response of other patients would help them to halt tumoural development.” This is a significant finding as it opens up a whole new potential route for developing therapeutic treatments across a broad range of cancers.

Searching with single cells

As well as opening up new treatment options, the future applications of this research also lie in early diagnosis. Using single-cell analysis, the team were able to see how a single, rapidly proliferating lymphocyte eventually developed into a tumour.  “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,” said first author Carolina Villarroya-Beltri.

They suggest that by using this approach, researchers would be able to capture and study the earliest stages of a cancer and use the information to identify cells with tumour potential before anything shows up on clinical tests.

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