‘Fingerprints’ of childhood cancer treatment provide clues that may help mitigate second cancers

Scientists at St. Jude Children’s Research Hospital today report how lifesaving childhood cancer treatments leave “fingerprints” on DNA, which can lead to second neoplasms (cancers or cancer-like diseases) decades later. The discovery may provide a path toward reducing long-term risks of pediatric cancer therapy by improving surveillance and early detection of secondary disease for survivors. The findings were published today in Cancer Discovery, a journal of the American Association for Cancer Research. 

Childhood cancer survival has improved dramatically, but many survivors face long-term health risks well into adulthood. Until now, the direct biological link between specific pediatric cancer therapies and subsequent neoplasms has been difficult to define. To address this gap, St. Jude researchers analyzed genetic mutations in the subsequent neoplasm tumor tissue of 160 survivors who developed subsequent breast, thyroid malignancies and mengiomas, searching for patterns tied specifically to earlier treatments. 

“We found that lifesaving radiation and chemotherapy treatments that cure childhood cancer also leave specific mutational signatures or ‘fingerprints’ in the DNA of second neoplasms,” said first and corresponding author Samuel Brady, PhD, St. Jude Department of Pharmacy & Pharmaceutical Sciences. “These findings give us an opportunity to rethink how therapies are delivered to reduce risk, while also improving screening protocols to detect secondary cancers earlier.” 

Finding childhood cancer treatment’s DNA fingerprints

While previous research had linked certain therapies, such as radiation, to survivors’ increased cancer risk, this new study establishes a direct molecular connection. To find these direct connections and rule out normal aging-related mutations, the researchers looked at whole-genome, whole-exome and RNA-sequencing of second neoplasm samples from survivors enrolled in the Childhood Cancer Survivor Study (CCSS). They then compared those sequences to similar cancers in the general population, revealing recurring mutational patterns in survivors who received specific treatments. 

“We are the first to show direct causality between childhood cancer treatments and second neoplasms,” said co-senior author Jinghui Zhang, PhD, St. Jude Department of Computational Biology. “We found that the DNA-mutating effects of treatments are imprinted into the genomes of secondary cancers that emerged 20 to 30 years later, giving us new insights into how we could reduce treatment toxicity.” 

Radiation therapy was associated with the most frequent and largest DNA alterations, as well as the highest risk of secondary thyroid cancer. Chemotherapy agents also left identifiable signatures. Nitrogen mustards and platinum-containing agents caused smaller changes in DNA. However, the location of these mutations differed by drug type, which could lead to different outcomes. For example, platinum agents sometimes preferentially mutated the gene NF2, leading to a greater risk of a brain tumor called meningioma. These therapy-specific patterns could help clinicians anticipate which secondary cancers are most likely to develop. 

“In the last few decades, we have been very effective in developing treatments that save children’s lives,” said David Ellison, MD, PhD, FRCP, FRCPath, FRCPCH, St. Jude Department of Pathology chair. “By defining how these therapies mutate DNA in predictable ways, we can better understand and address the long-term consequences of these treatments.”