New insights into why some children with rhabdomyosarcoma (RMS) develop aggressive disease despite being classified as non-high-risk have been uncovered. The discovery could help clinicians identify children with potentially lethal disease at diagnosis and tailor their treatment accordingly. Published today (19 August) in Cancer Research, the study by researchers at the Wellcome Sanger Institute, the University of Cambridge, Great Ormond Street Hospital (GOSH), University College London and their collaborators investigated the genetic drivers of RMS — an aggressive type of cancer that develops from muscle tissue. It is one of the most common soft tissue cancers in children under the age of 15 with around 55 children being diagnosed in the UK every year.1 Unlike many adult cancers, which are often linked to ageing or environmental factors, childhood cancers usually arise from changes that occur during development that increase the risk of cancer. RMS is broadly split into two different types, depending on whether the tumour contains a genetic risk marker. This marker is a fusion of two genes that are not normally connected. In patients with this marker, survival is substantially lower than in those who do not carry it, despite intense treatment.2 However, some children whose tumours do not carry the high-risk marker still develop aggressive disease, and it is unclear why this happens. In a new study, researchers at the Wellcome Sanger Institute, the University of Cambridge and their collaborators sought to understand why this group of non-high-risk patients go on to experience such an aggressive cancer. The researchers compared tumours of children with high-risk and non-high-risk disease, using cutting-edge genomic techniques to sequence and analyse cells.3 In particular, they used single-cell RNA sequencing, which is a technique that allowed the team to examine gene activity in individual cancer cells. This revealed the true aggressive face of cancer cells that had ordinarily been classified as non-high-risk. The team also used a method called spatial transcriptomics, which enabled the scientists to map where the cancer cells were located within the tumour, revealing how aggressive cell populations are organised within the cancer tissue.4 The study revealed that aggressive tumours of children who had been classified as non-high-risk have gene expression patterns that closely resemble those of high-risk tumours, despite lacking the genetic risk marker. They also found that children with non-high-risk tumours which behaved aggressively carry rare genetic changes that affect the same cellular pathways as high-risk tumours. This suggests that there are multiple genetic routes leading to the same aggressive tumours. By identifying unique markers of these high-risk cells, researchers hope to develop targeted therapies, including immunotherapy treatments such as CAR-T cell therapy, that could destroy cancer cells more precisely while reducing the side effects associated with conventional chemotherapy. Ultimately, the researchers envisage that these findings could help clinicians identify children at risk of aggressive tumours earlier, enabling more precise treatment for those most likely to relapse while avoiding unnecessary toxicity for other lower-risk patients. Researchers are now expanding the study to include hundreds of additional tumour samples, with the aim of identifying more of the rare genetic pathways that can lead to aggressive childhood cancer and accelerating the development of precision therapies for young patients. Dr Karin Straathof, co-senior author at UCL Cancer Institute and GOSH, said: "By studying tumours one cell at a time, we uncovered hidden populations of aggressive cancer cells that conventional methods miss. Although these tumours 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." 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 personalised 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 tumours 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." 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." |
