Whole Genome Sequencing Can Improve Childhood Cancer Care

Liam Davenport

November 09, 2021

Whole genome sequencing (WGS) can offer childhood cancer patients a more accurate diagnosis and prognosis, as well as suggest more targeted treatment options, suggests a UK pilot study of a national programme.

The researchers performed WGS, which is currently being rolled out in the National Health Service (NHS) as routine practice for childhood cancer in England, on 36 children with 23 different types of solid tumour.

Sequencing identified 51 reportable variants, which changed the diagnosis in four cases, improved the prognosis in eight cases, and revealed potentially beneficial treatments in seven cases.

Improved Diagnosis and Treatment

The research was presented at the 2021 National Cancer Research Institute (NCRI) Festival on November 8, and led by Patrick Tarpey, PhD, lead scientist for solid cancer in the East Genomic Laboratory Hub at Cambridge University Hospitals NHS Foundation Trust.

"Our results from this relatively small pilot group of children with cancer show how diagnosis and treatment can be improved," Dr Tarpey said in a press release.

"It suggests that offering whole genome sequencing to all children with cancer will provide more accurate information on diagnosis and prognosis, show whether there could be any hereditary cancer risk, and help inform treatment options."

However, the standardised central analysis of the WGS revealed only 39 of the reportable variants, with a further 12 identified via local inspection of the data by a local multidisciplinary molecular tumour board.

This, the authors say, "highlights the necessity for assiduous data analysis and expert clinical interpretation of centrally-derived variant calls, to maximise opportunities for individual children".

It will therefore be "important to establish processes for benchmarking the scientific and clinical interpretation of centrally-derived data". In addition, Dr Tarpey said that, as WGS is scaled up nationally, "we need to ensure we optimise all the steps in this process to reduce turnaround times and keep financial costs down".

Clinical Value

He told Medscape News UK that WGS for paediatric cancer is currently "available to clinicians across England as routine NHS care", alongside similar WGS assays for sarcoma and leukaemia.

These three indications, he noted, "are a prelude to other cancer types such as breast, brain, and ovary, which will also be available to clinicians in the future".

However, previous studies have suggested take up of genetic assays such as WGS can slow, and Dr Tarpey emphasised that studies "such as ours help demonstrate the clinical value whole genomes can deliver".

"In my experience, when oncologists, pathologists and geneticists have access to the ‘complete picture’ a whole genome provides, and they encounter examples of how this positively impacts patient care, they are keen to engage in the best interests of their patients."

He added that, "locally in Cambridge, we have a brilliant team of clinicians and scientists who are advocates of cancer WGS, and seek to take advantage of this assay whenever possible".

Double-edged Sword

David Kerr, professor of cancer medicine at the University of Oxford who was not involved in the study, sounded a note of caution, however.

He told Medscape News UK that WGS is a "double-edge sword", as this "small pilot suggests that potentially clinically useful data may be generated but that interpretation of these data requires multidisciplinary expertise".

Prof Kerr underlined that the study is "very small" and that the "projected clinical benefits are theoretical".

"We need real evidence that this approach will lead to treatment strategies which prolong survival and/or improve quality of life."

He added that the field of WGS will benefit from molecular tumour boards to "make the most of these data, and prospective clinical trials which are appropriately powered to demonstrate real-world benefit from this approach".

Study Details

The study forms part of the 100,000 Genomes Project to sequence 100,000 genomes from around 85,000 NHS patients affected by a rare disease or cancer.

The team recruited 36 non-consecutive children from two paediatric oncology units in the East of England, who had 23 different solid tumour types. Seventeen of the children had tumours primarily of central or peripheral nervous system origin.

The tumours underwent pathological evaluation, and tumour and germline DNA was sent to Genomics England for WGS and variant analysis, with the returned data evaluated locally at dedicated molecular tumour boards.

The standardised central reports of the genetic analyses revealed 39 reportable variants across the patient group, of which 36 were somatic and three germline.

Further examination of the source data, including manual inspection, revealed an additional 12 somatic variants in 10 cases.

Compared with standard of care genetic analyses, 75% of the reportable variants revealed by WGS were novel, and included enriched structural variants such as fusion genes in six cases.

WGS was also able to influence clinical decision making compared with standard of care assays, by refining the diagnosis in two cases and by changing it in another four cases.

It also provided prognostic information in eight cases, revealed novel therapeutic opportunities in seven cases and identified two pathogenic germline mutations.

Dr Julia Chisholm is chair of the NCRIs Childrens Group, based at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK, and was not involved in the study.

She commented in the press release that the study shows it is "feasible and beneficial to analyse the whole genetic code in children diagnosed with cancer".

"Whole genome sequencing helps us to be more precise in tumour diagnosis and to tailor treatments to suit individual patients as accurately as possible.

"As this innovation is introduced more widely, we hope that even more children will survive cancer," she said.

The study was funded by NHS England and the 100,000 Genomes Project, cancer programme.

No relevant financial relationships declared.

NCRI Festival: Abstract 3560. Presented November 8.


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