PREreview de Clinical Impact of Ultra-Fast Whole Genome Sequencing in Paediatric Haematology-Oncology Practice

General assessment

This is an interesting and clinically relevant study evaluating the feasibility and potential clinical utility of ultra-fast whole genome sequencing (UF-WGS) in paediatric haematology-oncology practice. The manuscript addresses an important limitation of current genomic testing: although whole genome sequencing can provide comprehensive molecular information, its clinical value may be reduced when results are not available within the timeframe in which important treatment decisions need to be made.

The authors evaluate UF-WGS in a real-world tertiary paediatric haematology-oncology setting and compare the workflow with NHS Genomic Medicine Service whole genome sequencing. The study includes 54 patients with a broad range of solid and haematological malignancies, comprising both prospectively recruited and retrospective cases. The combination of analytical comparison, turnaround-time assessment, and evaluation of potential clinical impact makes the study particularly valuable from a translational perspective.

Overall, the manuscript provides encouraging evidence that comprehensive genomic information can be generated within a timeframe that is much more compatible with routine clinical decision-making in paediatric oncology.

Strengths of the study

A major strength is the clear clinical focus of the work. Rather than examining sequencing performance only under laboratory conditions, the authors evaluate UF-WGS in patients undergoing investigation and treatment within an established paediatric oncology service. This increases the relevance of the findings to future clinical implementation.

The reduction in turnaround time is particularly impressive. UF-WGS achieved a mean turnaround time of approximately three days compared with 37 days for GMS-WGS. In paediatric oncology, where diagnostic classification, risk stratification, surgery, chemotherapy, or targeted treatment may need to be determined rapidly, this difference has potentially important practical implications.

The analytical concordance is also encouraging. UF-WGS recalled 143 of 151 clinically actionable somatic and germline variants identified through standard testing, corresponding to approximately 95% recall. In addition, UF-WGS identified 19 clinically actionable variants that were not identified by GMS-WGS. These results suggest that the faster workflow does not simply provide genomic information more rapidly but may also contribute additional clinically relevant information.

Another strength is the inclusion of both prospective and retrospective cohorts. The prospective cohort provides evidence of how UF-WGS can function within contemporary clinical practice, while the retrospective cases allow the authors to examine a broader range of molecular abnormalities and clinically informative scenarios.

The clinical-impact component is particularly interesting. In 18 of 35 prospective cases, UF-WGS was associated with improvements in clinical care, while clinicians considered that 9 of 19 retrospective patients could have benefited if UF-WGS had been available in real time. These findings help move the discussion beyond analytical performance and illustrate why turnaround time is clinically important.

The examples presented throughout the manuscript are useful in demonstrating how rapid genomic information can contribute to diagnosis, risk stratification, therapeutic decision-making, and avoidance of unnecessary interventions. This patient-level perspective makes the manuscript accessible to both genomic scientists and clinicians.

The additional flowcell proximity information is another interesting aspect of the study. The ability to obtain additional information concerning genomic structure and difficult genomic regions from the same sequencing workflow could potentially expand the clinical value of WGS without requiring multiple separate molecular assays.

Comments and suggestions

The manuscript is generally clear and well organised. I have several suggestions that may further improve its presentation.

First, it may be helpful to provide an even clearer description of how “clinical impact” was defined. The individual examples are informative, but a concise predefined classification of clinical benefit—for example, change in diagnosis, change in treatment, altered risk classification, avoidance of an intervention, or provision of additional prognostic information—would make the clinical-impact analysis easier to interpret and potentially easier to reproduce in future studies.

Similarly, presenting the prospective clinical benefits according to these categories in a table could be useful. This would allow readers to quickly understand which areas of paediatric oncology practice benefited most frequently from rapid genomic information.

Second, the turnaround-time findings are one of the strongest aspects of the manuscript. Additional information about the distribution of turnaround times, such as median, range, or interquartile range, alongside the reported mean could provide readers with a more complete understanding of workflow reliability. Demonstrating that rapid turnaround is consistently achievable will be particularly important for future routine implementation.

Third, the manuscript could potentially expand the discussion of how UF-WGS may integrate with existing diagnostic approaches. In current paediatric oncology practice, rapid targeted assays, cytogenetics, FISH, and other molecular tests may remain important in particular clinical situations. It would therefore be interesting to discuss whether UF-WGS is envisaged primarily as a replacement for multiple existing tests, as an early comprehensive genomic test supplemented by selected rapid assays, or as part of a combined diagnostic strategy.

The additional variants detected by UF-WGS are an interesting finding and could perhaps be described in slightly greater detail. A concise summary according to variant type and clinical relevance would help readers understand where UF-WGS may provide the greatest added value compared with existing workflows.

The manuscript appropriately acknowledges that this is a single-centre pilot study. This does not diminish its value as a feasibility study, but future multicentre evaluation will be important to determine how easily the workflow can be implemented across laboratories with different infrastructure, staffing, sample volumes, and clinical pathways.

Similarly, future studies assessing health-economic aspects would be valuable. Rapid comprehensive sequencing could potentially reduce the need for sequential molecular tests, shorten diagnostic pathways, and prevent unnecessary procedures. Evaluation of these potential benefits alongside sequencing and computational costs would provide important information for healthcare systems considering wider implementation.

Finally, longer-term clinical outcomes would represent a natural next step for this work. The present study provides convincing examples of how rapid genomic information can influence or potentially improve management. A future prospective study examining endpoints such as time to definitive diagnosis, time to treatment decision, number of additional diagnostic procedures, length of hospital stay, treatment modification, and patient outcomes would provide complementary evidence for the clinical value of the approach.

Conclusions

This is a strong translational study addressing a practical barrier to the implementation of whole genome sequencing in paediatric oncology. The authors demonstrate that UF-WGS can provide clinically interpretable genomic information within approximately three days while maintaining high concordance with established genomic testing and identifying additional clinically actionable findings.

An important contribution of the manuscript is the demonstration that genomic turnaround time is not simply a laboratory performance metric but can have direct relevance to patient management. The prospective clinical examples illustrate situations in which having comprehensive genomic information early in the diagnostic pathway may influence meaningful clinical decisions.

The study also demonstrates the feasibility of introducing a rapid WGS workflow into a tertiary paediatric haematology-oncology service, providing a useful foundation for larger prospective and multicentre evaluations.

Overall, the findings are encouraging and support further investigation of UF-WGS as a tool for rapidly integrating comprehensive genomic information into paediatric cancer care. The manuscript should be of interest to clinicians, genomic scientists, molecular pathologists, and researchers working on precision oncology and implementation of genomic medicine.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they used generative AI to come up with new ideas for their review.