Genomic Fingerprints Reveal Early Chemotherapy Resistance in Childhood Cancer

Chemotherapy remains central to treating childhood cancers, yet its toxic effects can injure healthy tissues, and some tumors later relapse or spread. Clinicians have lacked early molecular markers that indicate when resistance is emerging during therapy. Distinct patterns of DNA damage left by cancer drugs could provide a trackable signal in real time. A new study shows that therapy-induced genomic “fingerprints” can appear within months in many pediatric tumors, suggesting a path toward more precise monitoring of treatment response.

The Hospital for Sick Children (SickKids; Toronto, Canada) led an international analysis that used whole-genome sequencing (WGS) and advanced computational methods to detect distinct genomic “fingerprints” left by common chemotherapies. The approach paired tumor WGS with detailed treatment exposure and clinical data to map drug-specific patterns of DNA change over time. Researchers say these signatures can be tracked to identify cancers that are evolving in ways that make them more likely to resist treatment, spread or return later.

Investigators performed extensive computational genomics to identify subtle patterns and connect them to specific therapies. The work drew on detailed information about therapy type, dose, and timing contributed by families participating in the Kids Cancer Sequencing (KiCS) program. In the study, genomic signatures, described as records of how cancer cells responded to therapy, were interpreted and translated so they could be followed longitudinally during and after treatment.

The study examined more than 600 tumors from 544 patients across Canada, Australia, and the United States and was published in Nature on July 22, 2026, Distinct chemotherapy-associated signatures appeared as early as 91 days after treatment began. Within 18 months, 48% of tumors had a detectable platinum-related signature in surviving cancer cells. The team validated the findings in independent datasets that included adult patients. Researchers say the study exemplifies a precision approach that integrates genomic information with treatment history to better understand how therapy shapes tumor evolution.

According to the team, the identified signatures may serve as biomarkers to create a potential early warning system for children undergoing chemotherapy. They add that, in the future, this line of work could enable a blood test for patients of any age who receive chemotherapy. Researchers believe these insights could support more tailored decisions, including de-escalation of therapy when appropriate.

“Every tumor is unique and is driven by its own biology based on where it originated and how it evolved. 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,” said Dr. Adam Shlien, senior scientist, Genetics & Genome Biology, and a lab director in Genome Diagnostics at SickKids.

“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," says first author Dr. Mehdi Layeghifard, Senior Research Associate in the Shlien Lab.   

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