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Cancer leaves a molecular imprint on the body from the moment it develops. Like the breadcrumbs that Hansel and Gretel dropped along the paths to remember the way back home, tumors also leave a trace of their route, signals that now allow scientists to travel that path in reverse to understand the origin. of a cancer. A study by researchers at the Barcelona Biomedical Research Institute (IRB) published this Tuesday in the journal Cancer Discovery It expands on the understanding of childhood cancer and explores the origin of the second tumor in four pediatric cancer patients. Each case is the paradigm of a different onset pattern, but, for the first time, researchers have also described mutations caused by chemotherapy in healthy tissue with unknown long-term effects.
If the appearance of cancer in childhood is already rare – there is one for every 200 in adults – the fact that the same child develops two different tumors in pediatric age is an unusual situation. Above all, if they do not have any underlying genetic disease that predisposes them to developing tumors. “They are very exceptional cases and extremely surprising for oncologists. Very little happens,” contextualizes researcher Núria López-Bigas, leader of the IRB group that carried out the study. At the Sant Joan de Déu Hospital in Barcelona, where the cases analyzed come from, more than 4,000 children with cancer have been treated in the last 20 years and only thirty respond to this circumstance of developing two tumors completely independent of each other (the second it is not a relapse of the first) during childhood.
According to López-Bigas, the big question they posed was whether these two tumors in each child had something in common. For example, if they shared a similar origin, such as mutations in cell lineages (a set of cells that come from the same stem cell) from embryonic stages; or if, perhaps, the toxicity of the treatment during the first tumor could be involved in the appearance of the second. Unlike in adults, childhood cancer is not usually influenced by environmental factors, but rather is usually alterations in embryonic development.
With advanced genomic sequencing and bioinformatics techniques, scientists have been able to read the mutations that tumor cells have generated and review part of their history. “These tools allow us to reconstruct the history of these tumors, we reveal a part of the development of the cells. We don’t see it as a movie, but we reconstruct part of its history. The techniques we have used are like a window to the past,” explains the scientist.
Researchers have been able to learn, for example, how two cell lineages suddenly separated over time, giving rise to two tumors. And they have also been able to identify the trace left by platinum, a type of chemotherapy. “If a cell receives platinum, it damages its DNA and accumulates platinum mutations. And since we know the day the chemotherapy was administered, we can know the day those mutations were generated. It is like a fingerprint that allows us to know if clonal expansion [cuando una célula con mutaciones empieza a expandirse y genera muchas células hijas con las mismas mutaciones] that gave rise to the second tumor occurred before or after treatment.” The result of the investigation revealed a diverse origin of the second tumors.
The techniques we have used are like a window to the past: they allow us to reconstruct the history of these tumors”
Núria López-Bigas, researcher at the Barcelona Biomedical Research Institute
The first patient described is the only one where a closer link has been seen between the impact of chemotherapy and the appearance of the second tumor. At just over 13 years old, he suffered from rhabdomyosarcoma – a type of tumor that affects soft tissues, such as muscles. After treatment with chemotherapy, surgery and radiotherapy, he was cured, but at age 17 he developed acute myeloid leukemia related to the treatment. In the molecular study, the authors found mutations linked to platinum in all leukemia cells, which can only be explained, the researchers point out, if that second tumor originated from a cell that expanded after exposure to that chemotherapy. . “What we see is that all leukemia cells share mutations with a single cell after treatment. That means that the tumor was not there before, but we are very cautious: we can say that a clonal expansion of the tumor was done after the treatment, but no causal study has been done,” López-Bigas specifies. In any case, treatment-related acute myeloid leukemia is one of the most common secondary tumors among treated patients and accounts for between 7% and 8% of all myeloid leukemias detected.
Same mutation, different paths
Another of the cases studied – a child who developed a rare brain tumor at 10 months of age and another different brain cancer more than eight years later – shows a common origin of the two tumors, explains López-Bigas: “We analyzed the complete genome of the two tumors and we look at how many mutations there are in common. There were five. There are very few of them, which indicates that they occurred very early on, during the first phases of development. But within these mutations, one is the cause of cancer.” The mutation that fueled the onset of both diseases occurred in early stages, but the tumors followed different paths.
In this case, chemotherapy does not appear to have played a role. “During the treatment of the first tumor, the cells [del segundo] received mutations, but different cells have different mutations caused by platinum, which indicates that the cells of the second tumor had already begun to expand before the treatment,” concludes the expert. If clonal expansion had begun after treatment, the platinum mutations in the tumor would be the same in all tumor cells. The findings show that the tumors originated at the same time, but the second continued to accumulate mutations and expanded slowly for years “until it became clinically evident,” the scientific article states.
In the other two cases analyzed the origin of the tumors is different. Two random mutations during embryonic development led to the appearance of the tumors at different times in their lives. “These two cases fall into bad luck or we just don’t fully understand it. But it does not seem that the treatment of the first is involved in the second and the tumors do not share anything that happened in the early stages of development. They are mutations driver [las que conducen al cáncer] different,” says López-Bigas. The information obtained from one of these patients, however, has been key to delving into the long-term impact of the drugs.
Martha’s legacy
Her name was Martha. She was 17 months old when she was diagnosed with neuroblastoma and, despite the aggressiveness of the tumor, she was cured. But at the age of 10 she was diagnosed with another brain cancer and she died on August 12, 2019. Her parents, Rosa Pascual and Jordi Gual, authorized samples of her tumor and other organs to be taken for investigation. what had happened. “Apart from knowing what happened to Marta, if with this we can help other families, it helps you a little to make sense of what is happening,” says her mother.
Analysis of samples from the girl’s unaffected organs revealed, for the first time, the accumulation of mutations throughout healthy tissue due to chemotherapy. “Mutations accumulate and many of these do not have an important implication in people’s lives, but the question remains open as to what role they may have in the evolution of cancer survivors,” says López-Bigas.
The origin of the tumors dates back to the first weeks of pregnancy: there is a process of cell replication so complex and brutal that there are errors. Spontaneous mutation exists without anyone doing anything. “It is a natural biological error.”
Jaume Mora, pediatric oncologist at Hospital Sant Joan de Déu in Barcelona
Jaume Mora, pediatric oncologist at Sant Joan de Déu and co-author of the research, explains that “chemotherapy is an agent that kills cells because it generates alterations in their DNA.” Thus, it manages to destroy malignant cells, but also leaves a mark on healthy ones. “Thanks to this autopsy, we saw the signature that these types of drugs induce. All the fabrics had the DNA mark of the platinums received nine years earlier. And now, this opens a whole book of what happens after many years. We do not know the mechanism by which the damage occurs. But DNA damage persists for at least 10 years, and it is possible that this damage explains long-term effects,” agrees the oncologist.
López-Bigas urges caution in interpreting the study’s findings. “Chemotherapy, especially in childhood cancer, saves many lives: children are cured and have 70 or 80 years ahead of them. But there is epidemiological evidence that there are side effects due to the treatment that manifest years later, such as an increased risk of tumors or cardiovascular effects,” she contextualizes. What is not clear, in the eyes of scientists, is how chemotherapy causes these effects. “At a cellular and molecular level, what chemo does to our cells is not clear and we want to know. “One of the things it does is generate mutations,” she explains, but its role in health and disease is still unknown.
Lucas Moreno, head of pediatric oncology at Vall d’Hebron Hospital, calls the research “interesting and very elegant.” “What is new is that the life tree of the cells is documented. As genomics and this type of characterization improve, knowledge will improve to understand what happens in childhood cancer,” he reflects. Regarding a potential impact of chemotherapy on the development of a second tumor, the doctor, who has not participated in the study, points out: “Chemo and radiotherapy are essential to cure children. Thanks to their existence, 85% are cured. Its effects are being monitored better and better and we are going to move forward to adjust to the minimum that each patient needs.”
“A small step that opens more questions”
For his part, López-Bigas warns that this study “does not change anything in clinical practice tomorrow,” but it is “a small step that opens up more questions.” “We don’t have a final conclusion. Each patient is a different conclusion. And the question is what the mutations linked to chemotherapy do in healthy tissue.” Research, he adds, “contributes to the understanding of cancer and emphasizes the importance of improving treatments”: “We must think that, once cured, the patient has a very long life ahead of him and his quality of life must be guaranteed.” life”.
Mora emphasizes that understanding the origin of tumors “is important for families.” “This explains that the origin of the tumors dates back to the first weeks of pregnancy and, furthermore, it is not transmissible. At that moment there is a cell replication process so complex and beastly that there are errors. Spontaneous mutation exists without anyone doing anything. It is a natural biological error. Here there is no intervention from the father or mother,” explains the oncologist. And knowing that information, he asserts, helps many families “to live in peace.”
Marta’s parents attest to this. Knowing the origin of her daughter’s tumors helped them. “It leaves you with peace of mind that it was inevitable. And if we have been able to facilitate the investigation, although it will no longer be useful for us, it does comfort us to think that Marta’s death was not in vain,” says Gual.