A new study has demonstrated how advanced techniques such as cell-free DNA (cfDNA) sequencing can uncover the complex genetic and epigenetic factors that cause aggressive paediatric cancers and their recurrence. This could support diagnosis, provide prognostic information and pave the way for new targeted novel therapeutics.
Oncologists from the Institute of Cancer Research in London showed that cfDNA sequencing can give a more complete picture of how a tumour develops over time and how it can adapt and change in response to treatment.
They profiled a large, diverse cohort of children with relapsed or progressive solid tumours, analysing matched samples taken at diagnosis and relapse. They sampled both tumour tissue and paired plasma-derived cfDNA, which contains fragments of circulating tumour DNA (ctDNA).
Both sampling methods revealed the same types of genetic mutations, and serial tumour sequencing identified genetic and epigenetic drivers of relapse. However, if sufficient ctDNA was present, cfDNA sequencing captured a wider spectrum of mutant alleles and a higher degree of intra-tumour heterogeneity. Heterogeneity can explain why some tumours resist treatment.
In some patients, cfDNA sequencing could detect additional DNA mutations missed by the original tumour biopsy. Since cfDNA sequencing only requires a blood sample from the patient, it is much less invasive than a tumour biopsy, which usually requires a general anaesthetic, and can offer enhanced clinical information. It is also relatively low cost and has the potential to be applied serially and at scale, the researchers said.
The value of cfDNA analysis
This study, the Stratified Medicine Paediatrics (SMPaeds1) programme, shows the value of cfDNA analysis for children with cancer. It offers multiple potential applications including supporting diagnosis, providing prognostic information, identifying epigenetic targets for novel therapeutics, and the potential for serial sampling to understand how specific therapies alter epigenetic programming, the researchers concluded.
They are now working with colleagues across Europe to transfer the availability of cfDNA sequencing from research to clinical settings.
A future study, SMPaeds2, will investigate blood cancers and solid tumours in children and young people, including cancers of the brain, muscle and bone, which can be more challenging to access, diagnose and treat.
Reference
George, S. L. et al. Stratified Medicine Pediatrics: Cell-Free DNA and Serial Tumor Sequencing Identifies Subtype-Specific Cancer Evolution and Epigenetic States. Cancer Discovery. 2025, Feb. 04: DOI: 10.1158/2159-8290.CD-24-0916.
