An international study on children who relapse with cancer has provided clear evidence that DNA damage caused by cancer treatments leads to important changes in the genome of tumours over time, influencing how they respond to treatment and helping explain how they can later return and spread.
The findings of the study — a collaboration between scientists in Australia, Canada and the USA, published in the prestigious journal Nature — could have important implications for the treatment of childhood cancer, which affects more than 1200 young Australians each year.
It is well known that the use of certain therapies to treat childhood cancer can lead to a range of serious long-term health conditions in survivors, including second cancers. However, the precise amount and nature of DNA damage caused by chemotherapy is not well understood, nor its effect on relapse and metastasis. To address these gaps in knowledge, researchers studied the genomes of more than 600 tumours from children with high-risk cancer enrolled on three precision medicine programs, including Australia’s Zero Childhood Cancer Program (ZERO).
Focusing on ‘mutational signatures’ — characteristic patterns of mutation (DNA changes) resulting from exposure to different chemotherapeutic drugs — they showed that childhood cancers at relapse carry nearly three times as many of these signatures, and around twice the total number of somatic mutations, compared with treatment-naive tumours. Platinum-based drugs were the strongest contributors to these changes, driving about 60% of all therapy-related mutations. In total, 69 distinct signatures were found to operate in childhood cancer — 30 more than previously reported.
By linking genomic data to detailed treatment records, the researchers were able to show that some treatment-related mutations are detectable as early as one year into therapy, providing new insight into how cancers develop resistance to treatment, and highlighting opportunities for treatment de-escalation. Excitingly, these results also suggest the future possibility of using mutational signatures for the early detection of drug-resistant clones (sub-populations of cancer cells with acquired drug resistance) so they can be eradicated before becoming dominant and leading to disease progression.
‘These findings provide the clearest picture yet of the mutagenic effects of chemotherapies used to treat children with cancer, and new insight into how they shape disease at relapse,’ said Dr Noemi Fuentes-Bolanos, paediatric oncologist and clinical geneticist at Kids Cancer Centre, Sydney Children’s Hospital, and clinical scientist at Children's Cancer Institute, who was an author on the study*. ‘It is our hope that this fresh understanding will help guide future efforts to personalise therapy and improve outcomes for these children, including their long-term health.’
*Other Children’s Cancer Institute authors on the study included Dr Marie Wong-Erasmus, Dr Chelsea Mayoh & Prof Mark Cowley
Read the full paper online: https://www.nature.com/articles/s41586-026-10803-1
