Transforming Paediatric Oncology: The Impact of Whole Genome Sequencing on Diagnosing and Managing Haematological Malignancies
Authors: Shamma Menna , Zheleznyakova Elena , Chalker Jane , Khorashad Jamshid , Tewari Sanjay 
Published: December 2024

Background
Whole genome sequencing (WGS) is a transformative technique with significant potential to improve diagnosis and management decisions beyond the capabilities of conventional genetic testing methods. Despite challenges in fully understanding and interpreting the significance of some findings, WGS has shown substantial benefits in diagnosing and managing various paediatric cancer cases.
Aim
The study aims to compare data from standard of care molecular workups in newly diagnosed haematological malignancy patients with outcomes from whole genome sequencing testing. The goal is to highlight the significance of WGS in patient management.
Methods
Data was collected retrospectively for paediatric patients from August 2021 to June 2024, aged between 1 and 18 years old, using hospital electronic records. The collected data included patient age, diagnosis, results of standard molecular testing, and results of whole genome sequencing.
Results Patient Cohort: A total of 143 patients consented for whole genome sequencing (WGS), consisting of 90 males (63%) and 53 females (37%). The cohort included a variety of diagnoses, with the majority being B acute lymphoblastic leukaemia (ALL) at 73% (104 patients), followed by T ALL at 13% (19 patients), acute myeloid leukaemia at 8%, and other diagnoses at 6% (8 patients). The other diagnoses included mixed phenotypic acute leukaemia, juvenile myelomonocytic leukaemia, acute promyelocytic leukaemia, B non-Hodgkin lymphoma, and anaplastic large B cell lymphoma. Concordance with Standard Testing: WGS results were concordant with standard care testing, including Fluorescence In Situ Hybridization (FISH), in 123 cases (86%). Eight patients' WGS tests failed due to low tumour burden. Impact on Management: WGS results led to changes in management in 2 cases. These changes involved alterations in treatment plans, risk stratification, and the introduction of targeted therapies. Unexpected Mutations: Unexpected somatic mutations were identified in 34 cases, most of which were of unknown significance. Germline mutations were found in 4 cases, including 2 cases with BRCA1 mutations, 1 case with a RUNX1 mutation, and 1 case with a PALB2 mutation. All these mutations were reported as pathogenic and necessitated referral to a geneticist.
Conclusion
Routinely offering WGS to newly diagnosed children with cancer is a promising step towards better genetic mapping of childhood cancers. It is expected to have a positive impact on clinical practice and improve the quality of life for children and their families. the integration of WGS necessitates an in-depth comprehension of its results. Achieving this understanding mandates extensive research and inter-institutional collaboration, including the discussion of findings in Genomic Tumour Advisory Board (GTAB) meetings. Additionally, it is crucial for treating clinicians to develop a greater awareness of the clinical implications of WGS results, a goal that can only be realized through the study of larger patient cohorts.
Implications for Clinical Practice Enhanced Diagnosis: WGS can identify genetic anomalies missed by standard tests, providing a more comprehensive understanding of malignancies. Personalized Treatment: Identification of specific genetic mutations allows for more personalized and targeted treatment strategies. Research and Collaboration: Greater collaboration and larger studies are needed to better interpret WGS results and integrate them into routine clinical practice.
Recommendations Integration into Standard Care: Incorporate WGS into standard diagnostic and treatment protocols for paediatric haematological malignancies. Education and Training: Provide education and training for healthcare providers on the interpretation and clinical application of WGS results. Further Research: Conduct larger, multicentre studies to validate findings and improve the understanding of WGS data.
By embracing whole genome sequencing, we can enhance the precision of paediatric oncology care, offering hope for better outcomes and improved quality of life for young patients and their families.