Why some “lower-risk” childhood cancers turn deadly

Some childhood cancers may be far more dangerous than their initial risk classification suggests. Scientists have discovered that certain tumors considered less threatening can contain hidden populations of highly aggressive cancer cells, potentially explaining why some children experience devastating outcomes despite lacking the usual genetic warning signs. The discovery could change how doctors identify children at risk of life-threatening cancer, allowing treatment to be better matched to the true aggressiveness of their disease. The findings, published in Cancer Research, come from scientists at the Wellcome Sanger Institute, the University of Cambridge, Great Ormond Street Hospital (GOSH), University College London, and collaborating institutions. Their research focused on rhabdomyosarcoma (RMS), an aggressive cancer that develops from muscle tissue and is among the most common soft tissue cancers affecting children younger than 15. Approximately 55 children are diagnosed with the disease in the United Kingdom each year.[1] Unlike many adult cancers, which can develop after years of aging or exposure to environmental factors, childhood cancers often result from genetic changes that occur during early development. Why Some Childhood Cancers Defy Risk Predictions Doctors generally divide rhabdomyosarcoma into two main categories based on whether a tumor carries a particular genetic warning sign. This marker occurs when two genes that are normally separate become fused together, creating an abnormal genetic combination associated with especially aggressive disease.[2] Children whose tumors contain this fusion have substantially lower survival rates than those without it, even when they receive intensive treatment. But this classification has a troubling limitation. Some children whose tumors lack the high-risk genetic marker still develop aggressive cancers that can prove fatal. Until now, scientists have struggled to explain why these supposedly less dangerous tumors sometimes behave so aggressively. To investigate this mystery, the research team compared tumors from children with different forms of rhabdomyosarcoma, looking beyond the genetic markers traditionally used to estimate risk. The researchers examined tumor samples from 16 children, including four whose cancers lacked the fusion marker but proved fatal, four with fusion-positive tumors, and eight children with fusion-negative disease who remained alive. Hidden Aggressive Cancer Cells Revealed Using advanced genetic analysis, scientists studied the tumors at a level of detail that conventional techniques cannot easily achieve. One of their main tools was single-cell RNA sequencing, a technology that measures gene activity in individual cells. Rather than examining a tumor as a single mass, this approach allows researchers to investigate the behavior of its different cell populations and identify potentially dangerous cells that might otherwise go unnoticed. The scientists also used spatial transcriptomics, a technique that maps gene activity to specific locations within a tumor. This provided a clearer picture of where aggressive cancer cells were concentrated and how they were distributed throughout the tissue. The results revealed a striking similarity between tumors that had previously been placed in different risk categories. Some cancers classified as non-high-risk contained cells with gene activity patterns closely resembling those found in high-risk tumors. Even more surprisingly, these aggressive tumors did not need the same genetic mutations to produce similar behavior. Researchers identified rare genetic changes that affected many of the same cellular pathways involved in the most dangerous forms of the disease. This suggests that different genetic abnormalities can ultimately push cancer cells toward a shared aggressive state. In other words, tumors can reach a similarly dangerous biological condition through multiple genetic routes, even when they lack the warning sign typically used to identify high-risk disease. Dr. Karin Straathof, co-senior author at UCL Cancer Institute and GOSH, said: "By studying tumors one cell at a time, we uncovered hidden populations of aggressive cancer cells that conventional methods miss. Although these tumors carry different genetic changes, many converge on the same aggressive pathways. This helps explain why some children who appear to have lower-risk disease can still have a devastating outcome." A New Path Toward More Precise Cancer Treatment The findings could have important implications for how childhood cancer is diagnosed and treated. If doctors can identify the distinctive biological signatures of aggressive cancer cells at diagnosis, they may be able to recognize children who face a greater risk of relapse or death, even when standard genetic tests suggest otherwise. Such an approach could also help prevent unnecessary treatment. Children with genuinely lower-risk tumors might avoid some of the harmful side effects associated with intensive chemotherapy, while those with hidden aggressive disease could receive stronger or more targeted treatment earlier. The researchers are particularly interested in identifying markers that could be used to develop therapies aimed specifically at the most dangerous cancer cells. One possible direction involves immunotherapy, including CAR-T cell therapy. This treatment uses specially modified immune cells to recognize and attack cancer cells. Although such treatments would require further development and testing for rhabdomyosarcoma, they could eventually offer a more precise alternative to conventional chemotherapy, potentially reducing damage to healthy tissues. Scientists are now expanding their research to include hundreds of additional tumor samples. By studying a much larger group of patients, they hope to uncover more of the rare genetic changes capable of producing aggressive cancer and accelerate the development of personalized treatments. Sara Wakeling, Chief Executive Officer and co-founder of Alice's Arc, said: "Every child with cancer deserves the best possible chance of survival. We're proud to support research into rhabdomyosarcoma, showing how cutting-edge technologies can uncover the biology driving aggressive childhood cancers. These discoveries bring us closer to more personalized treatments and better outcomes for children." Dr. Laura Danielson, Children's and Young Person's Lead at Cancer Research UK, said: "Discovery research like this is essential to understand the unique biology of these cancers. This important study demonstrates that aggressive tumors may share similar features, even if they carry different genetic changes. By helping researchers understand what these high-risk cancers have in common, this work adds a vital piece to the puzzle and could help guide future efforts to improve treatment for children and young people with rhabdomyosarcoma." Rethinking How Doctors Identify Dangerous Childhood Cancers Beyond its potential treatment applications, the discovery challenges a fundamental assumption about how rhabdomyosarcoma should be classified. Instead of viewing aggressive disease primarily through the presence or absence of one genetic abnormality, the researchers suggest that doctors may need to consider the broader biological state of the cancer cells themselves. This distinction is important because tumors with different mutations can behave in remarkably similar ways. Identifying the shared features of aggressive disease could provide a more reliable way to recognize children who need intensive treatment, regardless of the particular genetic changes driving their tumors. Professor Sam Behjati, co-senior author formerly at the Wellcome Sanger Institute and Head of the Department of Paediatrics at the University of Cambridge, said: "This work changes how we think about rhabdomyosarcoma. Rather than a single, abnormal gene, we've shown that there is an overarching cell state of aggressive disease that defies conventional classification systems. Understanding this shared biology could help identify children who need more intense treatment to improve their survival." Although further research is needed before these findings can change routine clinical care, they provide a promising foundation for more accurate risk assessments and treatments tailored to each child's cancer. By revealing aggressive behavior hidden beneath seemingly reassuring genetic classifications, scientists hope to improve survival for children with the most dangerous tumors while sparing others from treatment they may not need. Research Notes and References Children with Cancer UK. Rhabdomyosarcoma Overview. Last accessed August 2026. Skapek, S. X. et al. (2013). 'PAX-FOXO1 fusion status drives unfavourable outcome for children with rhabdomyosarcoma: a children's oncology group report'. Pediatric Blood & Cancer. DOI: 10.1002/pbc.24532.The research received support through a Cancer Research UK -- Children with Cancer UK Innovation Award, with additional co-funding from Alice's Arc and funding from Wellcome.