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) on July 23. Researchers say these changes could eventually help clinicians spot treatment resistance earlier, before cancer returns or spreads, potentially allowing for more precise use of chemotherapy.
The study, published in Nature, 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 patterns appeared as early as 91 days after treatment began.
Among the findings was the impact of platinum-based chemotherapy. Within 18 months of treatment, 48 percent of tumors had a detectable platinum-related signature on surviving cancer cells. Over the past five decades, outcomes in childhood cancer have improved significantly with more than 85 percent of young patients surviving; however, chemotherapy's toxic effects can damage healthy cells and cause lifelong health consequences, including heart damage or secondary cancers years later.
"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," said 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 serve as records showing how cancer cells responded to therapy; now that researchers have recorded these unique signatures, clinicians can track them and identify cancers that are evolving toward resistance or recurrence.
"We spent years analyzing the data and developing new computational methods to pinpoint these subtle patterns and connect them to specific therapies," said Shlien. "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."
