Genomics research reveals millions of hidden mutations in childhood cancer

Childhood kidney tumours contain significantly more genetic mutations than previously thought, according to recent research.

The research, published in Nature Communications, focused on Wilms tumour, a type of kidney cancer that largely affects children under the age of five. An international team of researchers used a new, higher-resolution genome sequencing method called duplex sequencing to compare the number of genetic mutations in kidney tumour tissue with healthy tissue samples from the same children. They uncovered many more genetic changes than was previously possible with conventional DNA sequencing methods, which they hope could open doors to more precise and effective treatments for childhood cancers.

'Our findings suggest that childhood tumours have at least four times more genetic changes per cell than expected, which adds millions more changes per tumour, highlighting that what we could see before was just the tip of the iceberg,' said study co-lead Professor Sam Behjati, a paediatric oncologist and researcher working at the Wellcome Sanger Institute, the University of Cambridge, and Cambridge University Hospitals.

Duplex sequencing can detect genetic changes present in a single cancer cell, while traditional bulk sequencing only picks up mutations shared by a large proportion of cells.

The researchers studied tumour biopsies from five children with Wilms tumour, and found that Wilms tumours in babies were characterised by early genetic mutations which led to smaller sub-populations of genetically mutated cells in the developing tumour. This makes tumours in young children particularly susceptible to underestimates of mutation burden when conventional sequencing methods are used.

'With these latest genomic sequencing techniques, we can now see a much more detailed picture of Wilms tumour, which can occur in newborns,' said lead author Dr Henry Lee-Six, from the Wellcome Sanger Institute. 'This could help us understand this condition in more detail, and may change the way we view and treat childhood tumours as a whole.'

The discovery of high mutation burdens in Wilms tumour could expand the available treatment options for some childhood cancers. One possibility is immunotherapy, an approach which helps the body's immune system to target cancer cells, and is known to be more effective when tumours have a high number of genetic mutations.

The researchers also identified specific mutations which seem to play a key role in causing Wilms tumour. This could pave the way to personalised therapeutics tailored to specific genetic changes. Professor Behjati's previous research has highlighted the benefits of whole genome sequencing on real-life treatment outcomes for children with cancer (see BioNews 1246).