@article{a0a4cc84565843ebb8eb4d273832d404,
title = "Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia",
abstract = "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.",
author = "Ryan, {Sarra L.} and Peden, {John F.} and Zoya Kingsbury and Schwab, {Claire J.} and Terena James and Petri Polonen and Martina Mijuskovic and Jenn Becq and Richard Yim and Cranston, {Ruth E.} and Hedges, {Dale J.} and Roberts, {Kathryn G.} and Mullighan, {Charles G.} and Ajay Vora and Russell, {Lisa J.} and Robert Bain and Moorman, {Anthony V.} and Bentley, {David R.} and Harrison, {Christine J.} and Ross, {Mark T.}",
note = "Funding Information: Primary childhood leukaemia samples used in this study were provided by the Blood Cancer UK Childhood Leukaemia Cell Bank. We also thank all the members of the NCRI Childhood Cancer and Leukaemia Group (CCLG) Leukaemia Subgroup for access to material and data on clinical trial patients. This study was supported by Blood Cancer UK (grant 15036) and European Research Council (grant 249891). SLR is a Career Development Fellow supported by Cancer Research UK (CRUK) (grant C60802/A27193). CGM is supported by the American, Lebanese and Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital, and NIH CA197695 Funding Information: Primary childhood leukaemia samples used in this study were provided by the Blood Cancer UK Childhood Leukaemia Cell Bank. We also thank all the members of the NCRI Childhood Cancer and Leukaemia Group (CCLG) Leukaemia Subgroup for access to material and data on clinical trial patients. This study was supported by Blood Cancer UK (grant 15036) and European Research Council (grant 249891). SLR is a Career Development Fellow supported by Cancer Research UK (CRUK) (grant C60802/A27193). CGM is supported by the American, Lebanese and Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital, and NIH CA197695 Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = mar,
doi = "10.1038/s41375-022-01806-8",
language = "English (US)",
volume = "37",
pages = "518--528",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "3",
}