Chemotherapy drives mutation burden in relapsed childhood cancers
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A Nature study analyzing whole-genome sequences from a multi-institutional cohort finds that chemotherapy and radiotherapy are the dominant exogenous mutagens in relapsed childhood tumors. Post-therapy cancers carry nearly three times more private mutational signatures and twice the total somatic mutation burden compared to treatment-naive tumors.
The Study Design
Researchers used mutational signatures to measure DNA damage from therapy exposure in whole-genome-sequenced tumors from a multi-institutional cohort where therapy dose and total exposure were uniformly collected. Chemotherapy and radiotherapy were the only exogenous mutagens identified in relapsed childhood tumors and were often the dominant source of DNA alteration.
Key Findings on Mutation Burden
Post-therapy cancers carried nearly three times the number of private signatures and two times the total burden of somatic mutations compared with treatment-naive tumors. Platinum-based therapies, for which the study more than doubled the number of associated signatures, led to the highest number of variants in most patients. More than one-third of tumors treated with platinum drugs displayed detectable platinum signatures within one year.
Clinical Implications
The study provides genomic evidence for the critical mutagenic effects of chemotherapy in childhood cancer as a specific driver of tumor evolution. These data highlight opportunities for treatment de-escalation and the future possibility of tracking resistant clones before expansion.
What's Next
The findings may inform clinical trials testing reduced-intensity regimens for childhood cancers. It remains unclear how to balance the mutagenic risks of therapy against the need for effective tumor control.
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Chemotherapy drives mutation burden in relapsed childhood cancers
