Background Whole Genome Sequencing (WGS) enhances paediatric cancer diagnosis and management compared with standard molecular assays. However, its clinical utility could be further improved by reducing the National Health Service England (NHSE) turnaround times (TAT).

Methods We evaluated an ‘Ultra-Fast WGS’ (UF-WGS) workflow in a tertiary UK paediatric haematology-oncology unit. Children with suspected or confirmed cancer were recruited over two years (2023-2025), and their tumour, bone marrow and/or blood samples were sequenced on the UF-WGS workflow. All patients underwent concurrent NHSE Genomic Medicine Service (GMS) WGS, serving as the validation benchmark.

Results Of a total of 54 patients were recruited at diagnosis or relapse. UF-WGS reduced TAT to a mean of 3 days from sample collection, compared with 37 days for GMS-WGS. UF-WGS recalled 95% (143/151) of all clinically actionable somatic and germline variants not found standard NHS GMS-WGS testing. UF-WGS detected an additional 19 clinically actionable variants not found by GMS-WGS. Differences between the two workflows were attributable to tumour heterogeneity in some cases, and low variant allele frequency of those variants identified discrepantly.

Additionally, in 18/35 (51%) prospective cases, UF-WGS enabled demonstrable improvements in care. Clinicians independently judged that 9/19 (47%) of the retrospective cases would have clinically benefited from real-time UF-WGS. UF-WGS provided additional flowcell proximity data, which illustrated the potential to positively impact clinical care.

Conclusions This study indicates the feasibility and utility of UF-WGS and shows added benefits for the clinical management of paediatric cancers, with wider implications beyond this patient group.

Trial Registration 22/WA/0336

MM, SC, PG, ZK, JB, TN, IA, IV, MB, LF, JW, MR, DB and SH are or were employees of Illumina at the time of the study, a public company that develops and markets systems for genetic analysis.

22/WA/0336

https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ultrafast-whole-genome-sequencing-of-paediatric-cancer/

This work was supported by the Rosetrees Trust (AV, DHR), Addenbrookes Charitable Trust (AV), Isaac Newton Trust (DHR) and the NIHR Cambridge Biomedical Research Centre (NIHR203312).

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