Nearly half of childhood tumors treated with common types of chemotherapy showed detectable DNA changes linked to treatment within 18 months, according to a new international study led by The Hospital for Sick Children (SickKids). Researchers say these changes could eventually help clinicians spot treatment resistance earlier, before cancer returns or spreads, opening the door to a more precise use of chemotherapy. 

Published in Nature, researchers analyzed more than 600 tumors from 544 patients in Canada, Australia and the United States. By combining whole genome sequencing with detailed medical records and advanced computational methods developed at SickKids, the team found distinct genomic signatures of DNA changes left behind by different chemotherapies. Some of these patterns appeared as early as 91 days after treatment began. 

There's a long-standing belief that paediatric cancers are genetically quiet because they haven't had much time to mutate. Instead, it was mind-blowing to see how many mutations found in tumors that had relapsed or spread were linked to the chemotherapy used to treat the cancer in the first place." 

Dr. Adam Shlien, Lead Author, Senior Scientist, Genetics & Genome Biology and Lab Director in Genome Diagnostics at SickKids

Among the most striking findings was the impact of platinum-based chemotherapy, which is administered to nearly half of all treated cancer patients. Within 18 months of treatment, 48 per cent of tumors had a detectable platinum-related "signature" on surviving cancer cells. 

Can we reduce the risk of late effects?

Over the past 50 years, outcomes in childhood cancer have vastly improved, with more than 85 per cent of young patients surviving. Still, chemotherapy's toxic effects mean it can damage healthy cells and cause lifelong health consequences, including the risk of heart damage or another cancer years later. 

Such 'late effects' are uniquely impactful for children. 

"For a young patient with their whole life ahead of them, developing a secondary cancer or cardiac issue a decade later means confronting a new, life-altering crisis in their teens or twenties," says first author Dr. Mehdi Layeghifard, Senior Research Associate in the Shlien Lab. 

Until now, researchers have not known how much DNA damage is linked to chemotherapy exposure or when and how treatment-resistant tumors emerge in childhood cancer. Genomic signatures, or fingerprints, are records of how cancer cells responded to therapy and now that researchers have recorded these unique signatures, clinicians can track them and identify cancers that are evolving in ways that make them more likely to resist treatment, spread or return later. 

Study required new levels of computational analysis

In the study, researchers performed the kind of deeply intricate computational genomics needed to both interpret and translate the signatures that each cancer drug had left in the genome. 

"We spent years analyzing the data and developing new computational methods to pinpoint these subtle patterns and connect them to specific therapies," says Shlien, who says he believes this is the world's largest exploration of therapy signatures in childhood cancer using whole genome sequencing. 

The work was made possible because researchers had access to detailed chemotherapy exposure information, such as therapy type, dose and timing, from so many families, the majority of whom engaged in the SickKids Kids Cancer Sequencing (KiCS) program. 

One such family is the Gublers of Oshawa, Ont., who were shocked when their son Roman was diagnosed with lymphoma after visiting the SickKids emergency department last spring with an unrelenting fever. He was treated from May to September, successfully, and his lymphoma has been in remission ever since. 

"When we understood what it meant to be part of KiCS, to help hunt for new treatments, we were totally on board," says Nicole, Roman's mom. "Despite what he went through, Roman told me he's so proud to contribute to helping other kids. If my little nine-year-old boy can be part of such important research, then that's pretty wonderful." 

A potential early warning system

The Nature study exemplifies Precision Child Health, combining genomic information with treatment history to better understand how a therapy could affect a patient's cancer over time and adjust treatment to potentially reduce toxic effects. 

The findings are in fact a rare case of multiple levels of precision. 

"Every tumor is unique and is driven by its own biology based on where it originated and how it evolved," Shlien says. "When we treat it with chemotherapy, the interaction between tumor and treatment changes its makeup and evolutionary pathway. Defining that interaction could help clinicians detect important signals of future outcomes long before they become clinically visible." 

Researchers say the genomic signatures identified in the study may, in the future, act as biomarkers to create a potential early warning system for children undergoing cancer treatment. 

"Ultimately the goal is for clinicians to use these to identify those patients where they could de-escalate chemotherapy and intervene as early as three months if they see concerning genomic signatures," Layeghifard says. 

In the future, that could mean a blood test for patients of any age who face the need for chemotherapy. Importantly, the research team validated their findings in independent datasets, which included adult patients. 

"We ultimately believe these findings will have tremendous clinical value for adult cancers treated with similar drugs," Shlien says. 

Source:

Journal reference:

Layeghifard, M., et al. (2026). Prior therapy defines mutation profiles in childhood cancer at relapse. Nature. DOI: 10.1038/s41586-026-10803-1. https://www.nature.com/articles/s41586-026-10803-1