Abstract Background: Whole genome sequencing (WGS) improves childhood cancer management by detecting clinically actionable variants beyond the scope of standard assays. However, current turnaround times (TAT) are well beyond clinical decision-making windows. We developed a novel ‘Ultra-Fast Whole Genome Sequencing’ (UF-WGS) technology to deliver comprehensive genomic results within days, and evaluated its feasibility, accuracy, and clinical impact in real-world pediatric hematology/oncology. Methods: Children with suspected or confirmed malignancy in Cambridge were recruited between 2023–2025. Tumor, bone marrow, and/or blood samples were analysed with UF-WGS and standard genomic medicine service (GMS-WGS) concurrently. UF-WGS deploys Constellation mapped read technology, eliminating library preparation by applying crude lysate or DNA directly onto the flowcell surface providing enhanced genome coverage, variant calling and phasing. Variant calls and TAT were benchmarked against GMS-WGS. Only clinically actionable variants as per the UK national genomics test directory were reported. Clinical utility was assessed by multidisciplinary review. Results: Fifty-four patients representing the expected range of childhood malignancies were recruited. UF-WGS reduced mean TAT of clinically actionable WGS reports from 37 to 3 days. It recalled 95% of somatic and germline variants and detected 19 additional variants, leading to alterations in clinical management. Discrepancies were due to tissue heterogeneity or low variant allele frequency. Median sequencing depth of UF-WGS (137× tumor; 84× germline) was superior to GMS-WGS (97x tumor; 42x germline).UF-WGS enabled demonstrable clinical benefit including risk stratification, target identification and pharmacogenomic guidance in 18/35 (51%) of prospectively recruited patients. UF-WGS supported de-escalation of therapy, earlier initiation of targeted treatments and optimization of surgical timing. For one patient, rapid identification of a germline ACVR1 mutation allowed a diagnosis of fibrodysplasia ossificans progressiva, avoiding harmful interventions. In 9/19 (47%) retrospective cases, independent reviewers judged that real-time UF-WGS would have improved management.UF-WGS was particularly advantageous in leukemia, where tumor-only analysis avoided delays associated with obtaining germline DNA. The clinical value of delivering comprehensive cytogenetic, minimal residual disease, and pharmacogenomic data within 72 hours is particularly great in this disease setting. Conclusions: UF-WGS is feasible, accurate and clinically impactful in pediatric cancer, delivering real-time WGS to inform management decisions. It offers a scalable framework to consolidate multiple molecular assays into a single, rapid test, supporting ambitions for faster genomic diagnosis and equitable precision medicine delivery internationally. Citation Format: Aditi Vedi, Jamie Trotman, Joao Dias, Martina Mijuskovic, Sera Choi, Laura Kingham, Rachel Moore, Sarah M. Leiter, Rowena Guermech, Amanda Semerene, Aviva Grisby, Sophie Wool, Victoria Joslin, Zoya Kingsbury, Mark Ross, David Bentley, Sam Behjati, Sean Humphray, Patrick Tarpey, David Rowitch. UltraFast whole genome sequencing enables personalized treatments in childhood cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3493.
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