The keys to paediatric precision

Interestingly we found that if there is sufficient circulating tumour derived DNA present, then ctDNA sequencing will detect almost all the mutations detected in tumour tissue biopsy and many more not that were not detected. Importantly, we also showed that ctDNA sequencing can be useful to detect more aggressive subclones.

This means ctDNA analysis can add valuable information and that in some patients it can detect additional DNA mutations missed by tumour biopsy. This work is the largest study with matched ctDNA and tissue sequencing to date and shows the value of ctDNA testing for children with cancer.

It seems increasingly clear that driver mutations aren’t the only culprit for relapse, do you think the methods the group use can track epigenetic variations over time?

Childhood cancers are known to carry a lower mutational burden than adult cancers, and in many children with cancer the genetic driver of relapse or disease progression is unknown.

Epigenetic alterations are increasingly being recognised as being a key driver of aggressive disease in childhood cancers, therefore new technologies are needed to understand how epigenetic adaptations mediate treatment resistance. In this study we used fragmentomics analysis of ctDNA to identify open chromatin at transcription factor binding sites which allowed us to infer active transcription factor networks. We identified subtype specific activation of transcription factors relating to cell of origin and cell state.

This methodology holds potential for serial tracking of transcriptional changes in response to therapy.

You used low coverage whole genome sequencing for the recent study – what are the benefits of using this?

lcWGS is relatively inexpensive and broadly accessible giving the potential for it to be applied serially and at scale.

What are your hopes for the future of stratified treatment for childhood cancers?

That the development of new technologies which will give greater insight into the underlying biology of aggressive childhood tumours and this will lead to the identification of more effective, less toxic treatments.

In the SMPaeds2 clinical trial we will evaluate the value of reporting back ctDNA test results at the time of relapse or disease progression. This is the first step towards making ctDNA testing more widely available.