A Spanish woman who overcame 12 tumors, five of them malignant, before the age of 40 opens up new hopes for cancer research. The doctors and scientists who treated the patient cannot explain how she is still alive. The single case may help improve early diagnosis and lead to development of new cancer treatments.
Dr. Miguel Urioste remembers the first time he met the patient, who is now 36 years old and whose identity has not been revealed to protect her privacy. It was the year 2015. The patient had already undergone five cancer treatments for tumors in various organs and surgeries to remove other non-cancerous malformations. No one up to that point had tried to connect the dots to explain what was behind such a high cancer rate.
The woman was short, suffered from microcephaly (when a baby’s head is smaller than expected) and had skin tags. But she was intellectually in perfect condition, recalls Urioste, who was head of the Family Cancer Unit at the Spanish Cancer Research Center (CNIO) until her retirement in January. “We traced her family tree and everything seemed to be in order; parents and sisters had no problems; it’s [her case] it didn’t fit any known clinical picture,” he says.
The researchers analyzed several of the patient’s genes for common mutations that increase the risk of tumors. None showed defects. So they began searching using a technology only available in leading molecular biology research labs: single-cell sequencing. This system makes it possible to extract thousands of cells from the blood of the patient and her relatives and read the complete genome of each one of them.
The results of the investigation, published Wednesday in Progress of science, reveal that the single case was due to a genetic mutation that had never before been observed in humans. The woman had inherited from each of her parents a mutated copy of the MAD1L1 gene. The few scientific references to mutations in this gene come from studies with mice: if the animal had it, it never survived birth. “It was very difficult to understand how this woman could survive with this mutation; She had to have something else that would have helped her”, explains Marcos Malumbres, head of the Cell Division and Cancer group at the CNIO, who participated in the genetic studies of the patient and her family.
After a sperm fertilizes an egg and an embryo is formed, each cell carries within it the instructions to grow, multiply, transform into neurons, a heart or bone, and give rise to a healthy baby. Those instructions are the genome: a book containing three billion DNA letters structured into 46 chapters called chromosomes. This patient’s doubly mutated gene caused cell growth to go out of control. Some cells inherited many more chromosomes than they should and others much less. The body’s own safety mechanisms should have caused a miscarriage, but they didn’t.
The key to this woman’s survival seems to lie in her own illness. Up to 40% of her blood cells have too many or too few chromosomes, a type of defect known as genomic instability, which is a hallmark of cancer. The patient’s immune system had reacted to this threat with widespread inflammation. Her defenses were on continuous red alert. Her mutation caused her to suffer from cancer much more frequently, but her immune system was also highly stimulated, which favored better identification and destruction of tumor cells, explains CNIO biochemist Carolina Villarroya, lead author of the study . “His genetic defect of hers ended up protecting her. She was very well cured of all malignant tumors after surgery and treatments; partly thanks to her immune system,” she explains. The woman’s tumors also had high genomic instability, which is “a weak point” for her survival, adds the scientist.
The patient has not developed any tumor since 2014. She lives alone, has a job and leads a normal life despite having to be closely monitored by doctors. “I spoke with her a few days ago and she is fantastic,” says Urioste.
For now, the team has not named a new illness for the patient, as there is only one known case so far. Instead, researchers have included it in a group of rare genetic disorders known as mosaic variegated aneuploidy (MVA) syndrome. Until now, only three genes were known to cause MVA. People with the syndrome are at increased risk of cancer and may develop one or two tumors in their lifetime. But the fourth gene responsible for MVA, the mutation in MAD1L1, triggers more cancer than the others, says Urioste. “This is also the longest surviving patient with this type of disease, because most usually die in childhood,” he says.
The researchers believe the extraordinary case will help improve cancer diagnosis and develop new treatments. One of the most outstanding results is that researchers have managed to detect small colonies of cells that have chromosomal defects characteristic of leukemia. It may or may not be a precancer. This is the potential of single-cell sequencing, says Malumbres. “I think this technology should be in hospitals within 10 years.” But he adds that he would not like to be in the shoes of doctors who detect this type of genetic defect in a patient and cannot apply any treatment, since there is no cancer yet.
For Urioste, it is obvious what these doctors must do: monitor the patient more closely to detect cancer earlier than current methods allow, which would increase the chances of survival. Urioste says that “it is not uncommon” for a case of hereditary cancer to go unnoticed.
For his part, Villarroya points out that the study of the patient may reveal new ways of stimulating the immune system of patients so that it detects and eliminates tumors, a basic mechanism of immunotherapy treatments against cancer.
Ana Beatriz Sánchez Heras, a specialist in familial and hereditary cancer at the Spanish Society of Medical Oncology, who was not involved in the study, argues that the research has important implications. “It is a work that increases the knowledge of the multiple mechanisms and molecular pathways that favor the malignant transformation of cells. It will certainly have immediate clinical applications in the diagnosis and possibly treatment of cancers,” he says.
Jair Tenorio, a specialist in rare diseases of genetic origin at Hospital La Paz in Madrid, who discovered Tenorio syndrome, believes that the study patient may be among the people with the highest risk of known tumors in the world. “I think we are facing a new disease,” he says. But the last word, he explains, will be held by the OMIM, the world’s largest database of disorders of genetic origin. Maybe they decide what to call it.