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Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia

Lookup NU author(s): Sarra Ryan, Claire Schwab, Dr Richard Yim, Dr Ruth Cranston, Dr Lisa Russell, Professor Anthony MoormanORCiD, Professor Christine Harrison FRCPath FMedSci



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023, The Author(s).Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.

Publication metadata

Author(s): Ryan SL, Peden JF, Kingsbury Z, Schwab CJ, James T, Polonen P, Mijuskovic M, Becq J, Yim R, Cranston RE, Hedges DJ, Roberts KG, Mullighan CG, Vora A, Russell LJ, Bain R, Moorman AV, Bentley DR, Harrison CJ, Ross MT

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2023

Volume: 37

Pages: 518-528

Online publication date: 19/01/2023

Acceptance date: 22/12/2022

Date deposited: 06/02/2023

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Springer Nature


DOI: 10.1038/s41375-022-01806-8

PubMed id: 36658389


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