Big changes in DNA help cause childhood cancer

The researchers expect that their findings could help pick out children with faster growing forms of the disease, and eventually lead to more effective treatments for children with cancer. Jayne Hehir-Kwa, associate group leader of the Kemmeren group: ‘A lot more research is needed to translate our findings to the clinic, but it’s really exciting to open up this whole new area of genomics research in childhood cancer.’

Big, structural faults in the DNA are a hallmark of many forms of childhood cancer. For example, in some tumors two genes have fused together, or sections of DNA code are scrambled or mistakenly repeated many times. Such so-called structural variants can help in diagnosing the exact form of cancer. They can also inform a child’s prognosis, with more complex structural variants being linked to a higher risk form of cancer . But only some of these faults were known, for a limited number of childhood cancer types.

Surprising role

Scientists in the Kemmeren group at the Princess Máxima Center analyzed the entire DNA of 120 tumors from children  with one of five different forms of cancer, including neuroblastoma and Wilms’ tumor.  They looked at tumor samples from the Máxima’s Biobank, where tissue from children treated at the Máxima is stored for use in research. Using a technique called whole genome sequencing, the scientists found that  nearly half of the tumors contained complex changes to the DNA. Their research was recently published in the journal Cell Genomics.

‘I was surprised that structural changes to the DNA played such a large role’, says Hehir-Kwa. ‘It suggests these complex genomic changes are important in the origin of childhood tumors.’

In 42 of 56 tumors with a complex structural fault, the fault affected a gene known to drive the growth of that particular form of cancer. Importantly, children whose tumors had such complex driver gene faults were twice as likely  to die from their disease, or see their cancer grow or come back after treatment. This underlines the scientists’ idea that complex genomic variants could be an important clue to the prognosis of children with a solid tumor.

Promising new area of research

Hehir-Kwa: ‘We plan to work with our clinical colleagues in the Máxima to follow up with data on the treatment and outcome in children whose tumors contained complex structural variations. This could in future lead to new tools in diagnosing and picking out children with a high risk form of cancer. We also believe that complex structural variations could be valuable new targets for precision medicine. A lot more research is needed to translate our findings to the clinic, but it’s really exciting to open up this whole new area of genomics research in childhood cancer.’

Ianthe van Belzen worked on the study as part of her PhD research in the Kemmeren group. She now works as a postdoctoral fellow at the European Bioinformatics Institute in the United Kingdom. She says: ‘Our study is the first to look at complex structural variations in the genome of multiple childhood tumors. This was possible thanks to the Máxima’s central biobank,  where tumor samples of children treated at the Máxima are stored. I’m looking forward to further explore the role of complex structural variations in the next step of my career.’