Research led by the Hospital for Sick Children in Toronto shows chemotherapy and radiotherapy are key sources of mutations in relapsed childhood tumors and that different treatments leave distinct mutational signatures.
As described in Nature, across all mutations in these pediatric tumors, about 15% can be clearly traced to four chemotherapies, and most of that therapy‑linked damage comes from platinum drugs like cisplatin, carboplatin, and oxaliplatin.
After platinum chemotherapy, temozolomide, 5‑FU, and thiopurines were the next‑most clearly mutation‑linked drugs in this study, but each added only a small fraction of the total mutational burden compared with platinum drugs.
“Many of the drugs used to treat children with cancer cause unfortunate long term side effects, including heart issues and secondary cancers,” lead author Adam Shlien, PhD, told Inside Precision Medicine.
“These drugs can also lead to somatic mutations, although the total genomic burden of this wasn’t known. Whether these mutations are associated with drug resistance in childhood cancer was also mostly unknown.”
In this study, the researchers assembled a multi‑national precision‑oncology cohort of 611 tumors from 544 children and young adults enrolled in three whole genome sequencing‑based programs, focusing on aggressive, relapsed or metastatic cancer.
The team then looked at exposure to 86 types of therapy in 13 drug classes, as well as radiotherapy, and created a detailed record of cycle dates, doses, and routes of administration for each child. They also recorded the number of drugs or other treatments the cancer patients were exposed to, looked for mutation patterns in tumor DNA linked to specific chemotherapy agents and tracked when these first appeared after treatment.
“It was striking how many mutations are associated with therapy—when the tumor cells survive, they frequently acquire thousands of mutations and many of these are tightly linked to the type of therapy that was used,” explains Shlien.
Platinum drugs were the biggest contributors to tumor mutation signatures. They caused a large fraction of all therapy‑related mutations and left clear, characteristic mutation patterns that appeared in a short amount of time after starting treatment, sometimes in as little as three months.
Although the presence of mutations did not necessarily lead to drug resistance or relapse, tumors with strong platinum‑linked patterns often showed activation of genes known to help cancer cells resist treatment with platinum drugs.
This finding was confirmed in the pediatric study cohort and in adults with cancer treated with platinum chemotherapy. Patients whose tumors carried these patterns had worse outcomes when treated with platinum drugs.
This study opens the door to using these mutation patterns to guide care. This could include deciding when to avoid re‑using a drug, or when to consider lowering doses of mutagenic treatments like platinum chemotherapies in settings where cure rates are already high. It also shows that these treatment‑induced mutation patterns are not just signs of past therapy but can be an early warning of the emergence of drug‑resistant cancer cells.
“Now that we have comprehensively defined which therapy-associated mutation patterns are acquired in childhood cancer, and when they emerge, we can start to think about screening patients for these signatures for the early detection of drug-resistant clones,” says Shlien.
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