Benefits for children with suspected cancer from routine whole-genome sequencing

The past decade has significantly advanced our understanding of cancer-causing variants. Decreased cost and increased accessibility of DNA sequencing have led to its adoption in oncology. Whole-genome sequencing (WGS) is the most comprehensive single assay, providing a complete picture of all variant classes across the genome. Studies show WGS is particularly beneficial in pediatric oncology, where treatment is often genetically guided, and the genetic basis of some childhood cancers is relatively unknown. Research suggests WGS offers additional relevant information even when extensive molecular assays are already used. WGS is incorporated into clinical practice through various models, from supra-regional centers focusing on high-risk patients to national initiatives offering WGS to all children with suspected cancer. However, evidence supporting routine WGS use in pediatric oncology is limited, with past studies often focusing on select patient groups or non-consecutive cohorts. This study aimed to evaluate the benefits of routine WGS on clinical practice by analyzing data from two English NHS units that systematically deployed WGS for consecutive children with leukemia and solid tumors.

Existing literature demonstrates the clinical utility of WGS in specific high-risk pediatric cancer populations. Studies have shown its ability to identify actionable mutations and alter treatment strategies. However, there is a lack of robust evidence regarding the benefits of implementing WGS as a routine diagnostic test for all children with suspected cancer. Previous studies often selected specific high-risk groups or employed non-consecutive patient cohorts, potentially limiting the generalizability of their findings. This research builds upon the existing body of knowledge by assessing the impact of routine WGS on a larger, consecutive patient cohort, providing more comprehensive evidence of its practical application in pediatric oncology.

This observational study involved two English tertiary childhood cancer units: Cambridge University Hospitals (CUH) and Great Ormond Street Hospital (GOSH). CUH provided data on children with solid tumors, while GOSH contributed data on children with hematological malignancies. The study comprised two phases: an implementation phase with non-consecutive patients selected at the clinician's discretion, and a routine testing phase aiming to include all eligible patients. WGS was performed through the NHS England Genomic Medicine Service, with Genomics England handling centralized sequencing and variant calling. Turnaround time was tracked from test request to results availability for clinical decision-making. The study captured a broad spectrum of pediatric tumors, with the exception of axial skeleton neoplasms and some low-grade brain tumors due to service configurations. SOC molecular tests were compared with WGS results to assess concordance and identify additional findings. A detailed impact analysis categorized WGS findings based on their clinical significance: diagnostic, risk stratification, therapeutic opportunities, and management changes. Stringent criteria were used to ensure only uniquely WGS-attributable management changes were included. Statistical analysis focused on descriptive statistics and qualitative assessment of clinical impact.

The study included 282 tumors from 281 children. WGS-attributable variants led to changes in patient management in approximately 7% (20 out of 282) of cases. In 29% (83 out of 282) of cases, WGS provided additional disease-relevant findings beyond those obtained through standard-of-care (SOC) molecular tests. These additional findings provided clinical benefit in 24% (69 of 282) of cases, including aiding diagnoses, providing therapeutic opportunities, and leading to changes in management. WGS faithfully reproduced the results of all 738 SOC molecular tests performed. The study also identified several previously unknown genomic features of childhood tumors, including novel gene fusions and mutational signatures. For example, WGS revealed an ATNX1-NUTM2D gene fusion in an infant high-grade brain tumor, previously undescribed in children. The study also found UV light signatures in ALCL, suggesting a potential link between UV exposure and recurrence risk. Unexpected germline cancer predispositions were also frequently identified, offering opportunities for predisposition-directed therapy and cancer screening.

The findings demonstrate the clinical utility of routine WGS in pediatric oncology. Unlike previous studies focusing on high-risk patients, this study showed that WGS improved patient management even in children with mostly standard-risk diseases. This suggests that routine WGS could benefit all children with suspected cancer. The management changes were diverse, with unexpected germline cancer predispositions significantly impacting treatment decisions. While SOC testing could potentially negate some WGS benefits if an extremely extensive testing regimen were implemented, WGS offers a comprehensive approach with the potential for assay consolidation. The study highlights the potential for cost savings and increased efficiency due to tissue conservation, particularly valuable in pediatric oncology. The identification of novel genomic features demonstrates the potential for WGS to advance our understanding of childhood cancers.

This study provides compelling evidence for the integration of WGS into routine clinical care for children with suspected cancer. The findings indicate that WGS can significantly improve patient management by delivering actionable genomic insights beyond those provided by standard-of-care tests. Future research should focus on optimizing WGS turnaround times and integrating other genomic data, such as gene expression profiles, to further enhance the clinical utility of WGS in pediatric oncology. Furthermore, economic analyses are needed to assess the long-term cost-effectiveness of routine WGS implementation.

The study's turnaround times, although improving over time, did not always match those of other studies. The impact of slower turnaround times on clinical decision-making warrants further investigation. The current genomic service limits RNA assessment to panel sequencing for gene fusion detection, potentially missing additional clinically relevant information that could be obtained with more comprehensive RNA sequencing. The study's findings may be specific to the NHS England Genomic Medicine Service model and the two participating units. Finally, the study's observational nature limits the ability to establish definitive causal relationships between WGS findings and clinical outcomes.