A trailblazing research paper in Science Advances presents an unprecedented case of a person who had developed twelve separate tumors, including five of malignant nature, over less than four decades. Remarkably, the patient has continued to survive, even while harboring mutations in both copies of a critical cell division gene, MAD1L1. In animal models, such mutations previously resulted in embryonic fatality. Researchers propose that the patient’s routine generation of aberrant cells provoked a continuous immune response against these cells, which led to the surprising elimination of aggressive cancers.
This exceptional instance of a person outliving 12 tumors paves the path for improved early diagnosis and immunotherapy in cancer.
Scientists have found that the 12 tumors, five of which were malignant, are due to the patient inheriting mutations in a life-critical gene from both parents.
The patient’s immune system naturally triggers a robust anti-inflammatory response that combats the tumors; understanding this process could assist in stimulating the immune response in similar situations, according to the authors of the study.
The research also demonstrates how a cutting-edge technique—single-cell analysis—can identify tumors at very early stages, or a predisposition to them.
The individual at the heart of the study, published today in Science Advances, has lived a life unlike any other. The patient’s first tumor appeared when they were an infant, with additional ones forming every few years. In less than four decades, the individual has experienced twelve tumors, with at least five being malignant, each unique and located in different parts of the body. The patient also has skin spots, microcephaly, and other alterations. Marcos Malumbres, the leader of the Cell Division and Cancer Group at the Spanish National Cancer Research Centre (CNIO), acknowledges, “we’re still unable to comprehend how this individual could have progressed through the embryonic stage, or how they managed to overcome all these health issues.”
CNIO researchers, Marcos Malumbres and Carolina Villarroya at the CNIO. Credit: Laura Lombardia/ CNIO
Malumbres believes that studying this singular case provides “a method to identify cells with tumor potential long before conventional clinical tests and diagnostic imaging. It also offers a new approach to enhancing the immune response to a cancerous progression.”
Alterations in both copies of MAD1L1
When the patient initially visited the CNIO’s Familial Cancer Clinical Unit, a blood sample was drawn to sequence genes commonly involved in hereditary cancer, yet no alterations were found in them. The researchers proceeded to analyze the person’s whole genome and discovered mutations in a gene named MAD1L1.
This gene plays a crucial role in the process of cell division and proliferation. The CNIO team examined the impact of the detected mutations and determined that they cause changes in the number of chromosomes in cells—all human cells contain 23 pairs of chromosomes.
CNIO researcher Miguel Urioste, at the CNIO. Credit: Laura Lombardia / CNIO
In previous animal studies, it was observed that when mutations exist in both copies of this gene—one from each parent—the embryo doesn’t survive. Astonishingly, in this case, the person, despite having mutations in both copies, has survived and managed to live a life as normal as can be expected under the circumstances.
There has never been a documented case like this before. Miguel Urioste, the study’s co-author and the former head of the CNIO’s Familial Cancer Clinical Unit, says, “academically we can’t label it as a new syndrome since it’s the description of a single case, but biologically it is.” Other genes are known that, when mutated, alter the number of chromosomes in cells, but “this case is unique due to its aggressiveness, the rate of aberrations it produces, and the extreme susceptibility to a multitude of different tumors.”
How did the tumors vanish?
The research team was particularly intrigued by the fact that the five aggressive cancers developed by the patient vanished relatively easily. Their theory is that “the continuous generation of abnormal cells has elicited a chronic immune response against these cells, aiding in tumor elimination. We believe that enhancing the immune response in other patients could aid them in halting tumor growth,” explains Malumbres.
The revelation that the immune system can instigate a defensive response against cells with an incorrect number of chromosomes is, according to this CNIO researcher, “one of the most significant outcomes of this study, potentially introducing new therapeutic avenues in the future.” Seventy percent of human tumors comprise cells with an abnormal number of chromosomes.
Single-cell analysis for early diagnosis
To investigate the patient and related family members—several of whom carry mutations in the MAD1L1 gene, albeit only in one copy—the scientists utilized single-cell analysis technology. This method offers a level of information previously unimaginable.
It involves studying the genes “of each of the blood cells independently,” elaborates Carolina Villarroya-Beltri, CNIO researcher and the study’s primary author. Despite a variety of cell types in the sample usually being sequenced, “by analyzing thousands of these cells individually, we can investigate what is happening to each specific cell and the implications of these changes in the patient.”
The single-cell analysis unveiled—among other irregularities—that the blood sample contained several hundred chromosomally identical lymphocytes, indicating they originated from a single, rapidly proliferating cell. Lymphocytes are defensive cells that target specific invaders; occasionally, a lymphocyte proliferates excessively and disperses to form a tumor. This study’s single-cell analysis captures what may be the earliest stages of cancer.
Based on this discovery, the researchers propose that single-cell analysis could be employed to identify cells with tumor potential much before the emergence of clinical symptoms or detectable markers in analytical tests.
Reference: “Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility” by Carolina Villarroya-Beltri, Ana Osorio, Raúl Torres-Ruiz, David Gómez-Sánchez, Marianna Trakala, Agustin Sánchez-Belmonte, Fátima Mercadillo, Begoña Hurtado, Borja Pitarch, Almudena Hernández-Núñez, Antonio Gómez-Caturla, Daniel Rueda, José Perea, Sandra Rodríguez-Perales, Marcos Malumbres and Miguel Urioste, 2 November 2022, Science Advances.
DOI: 10.1126/sciadv.abq5914
The study was led by researchers Marcos Malumbres, who heads the CNIO Cell Division and Cancer Group; Sandra Rodríguez-Perales, who leads the CNIO Cytogenetics Unit; and Miguel Urioste, who was in charge of the CNIO Familial Cancer Clinical Unit until earlier this year.
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Frequently Asked Questions (FAQs) about Cancer Survivor Study
How many tumors did the individual in the study develop?
The individual developed twelve separate tumors, five of which were malignant, over less than four decades.
What gene was found to be mutated in the patient?
The patient was found to have mutations in both copies of a gene essential for cell division and proliferation, called MAD1L1.
What implications does this case study have for cancer research?
This unique case study provides new insights into early cancer diagnosis and immunotherapy. The understanding of how the patient’s immune system naturally triggers a robust response to combat the tumors could assist in stimulating the immune response in other similar cases.
What is the significance of the patient’s survival despite having mutations in the MAD1L1 gene?
The survival of the patient is significant because in animal models, mutations in both copies of the MAD1L1 gene usually result in embryonic fatality. This case thus presents a unique scenario in which the individual has survived despite such mutations.
What is single-cell analysis and why is it significant?
Single-cell analysis is a cutting-edge technique used to study genes of each blood cell independently. The technique offers a wealth of previously unattainable information, allowing researchers to investigate what is happening to each specific cell and the implications of these changes in the patient. This could be used to identify cells with tumor potential much before the emergence of clinical symptoms or detectable markers in analytical tests.
More about Cancer Survivor Study
- Science Advances: Link to the research paper
- Spanish National Cancer Research Centre (CNIO): Official website
- MAD1L1 Gene: Information from the NCBI database
- Immunotherapy: Information from the American Cancer Society
3 comments
wow! dis text is amazin! da fact dat dis person survived 12 tumors is mind-blowin! cancer research shud pay attention 2 dis case 4 early diagnosis & immunotherapy. #science #cancerresearch
omg, dis gene MAD1L1 sounds complicated! buh it’s so cool dat dis person survived despite da mutations in it! single-cell analysis sounds like sum futuristic stuff, rly helpful in findin tumors early. hope it leads 2 betta treatments! #genetics #research
dis study is mind-bogglin! i can’t even imagine survivin one tumor, but 12? wow! da immune system is truly amazin. dis research gives me hope 4 new ways 2 fight cancer & maybe one day we’ll find a cure! #cancersurvivor #immunotherapy