Whole Genome Sequencing Can Improve Childhood Cancer Care

Whole genome sequencing (WGS) could provide cancer patients in childhood with a more accurate diagnosis and prognosis, as well as suggest more targeted treatment options, a UK pilot study of a national program suggests.

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

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

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 at the East Genomic Laboratory Hub of Cambridge University Hospitals NHS Foundation Trust.

“Our results from this relatively small pilot group of children with cancer show how to improve diagnosis and treatment,” said Dr. Tarpey in a press release.

“It suggests that providing full genome sequencing to all children with cancer will provide more accurate information about diagnosis and prognosis, demonstrate whether there might be a hereditary cancer risk, and help inform treatment options.”

However, the standardized centralized analysis of the WGS revealed only 39 of the reportable variants, with an additional 12 identified through local inspection of the data by a local multidisciplinary board for molecular tumors.

This, the authors say, “emphasizes the need for diligent data analysis and expert clinical interpretation of centrally derived variant calls, to maximize 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, said Dr. Tarpey said as WGS scales nationally, “we need to make sure we optimize all steps in this process to reduce lead times and keep financial costs low.”

Clinical Value

He told Medscape News UK that WGS for pediatric cancer is currently “available to clinicians across England as routine NHS care”, alongside similar WGS assays for sarcoma and leukemia.

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

However, previous studies have suggested that genetic testing, such as WGS, can slow down, and Dr. Tarpey stressed that studies “like ours are helping to demonstrate the clinical value that whole genomes can deliver.”

“My experience is that when oncologists, pathologists and geneticists have access to the ‘complete picture’ that an entire genome provides, and they come across examples of how this is positively impacting patient care, they are eager to be in the best interest of their patients. “

He added that “locally in Cambridge, we have a brilliant team of clinicians and scientists who are champions of WGS against cancer, and are trying to take advantage of this test where possible”.

Double edged sword

However, David Kerr, a professor of cancer medicine at the University of Oxford in Oxford, UK, who was not involved in the study, sounded cautious.

He told Medscape News UK that WGS is a “double-edged sword” as this “small pilot suggests that potentially clinically useful data can be generated, but the interpretation of this data requires multidisciplinary expertise”.

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

“We really need evidence that this approach will lead to treatment strategies that prolong survival and/or improve quality of life.”

He added that WGS’s field will take advantage of molecular tumor boards to “make the most of this data, and appropriately supported prospective clinical trials to demonstrate the benefit of this approach in the real world”.

Study details

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

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

The tumors underwent pathological evaluation and tumor and germline DNA was sent to Genomics England for WGS and variant analysis, with the data returned being evaluated locally on special molecular tumor boards.

The standardized central reports of the genetic analyzes revealed 39 reportable variants across the patient population, 36 of which were somatic and three germline.

Closer examination of the source data, including manual inspection, revealed 12 more somatic variants in 10 cases.

Compared to the standard genetic analyses, 75% of the reported variants revealed by WGS were new, and in six cases included enriched structural variants such as fusion genes.

WGS was also able to influence clinical decision making compared to standard care assays, by refining the diagnosis in two cases and altering it in an additional four cases.

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

dr. Julia Chisholm is Chair of the NCRI’s Children’s 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 noted in the press release that the study shows that it is “feasible and beneficial to analyze the entire genetic code in children diagnosed with cancer.”

“Full genome sequencing helps us be more accurate in the diagnosis of tumors and tailor treatments as closely as possible to individual patients.

“As this innovation is more widely introduced, 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 indicated.

NCRI Festival: Abstract 3560. Presented on November 8.

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