Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

Claire Schwab; Ruth E. Cranston; Sarra L. Ryan; Ellie Butler; Emily Winterman; Zoe Hawking; Matthew Bashton; Amir Enshaei; Lisa J. Russell; Zoya Kingsbury; John F. Peden; Emilio Barretta; James Murray; Jude Gibson; Andrew C. Hinchliffe; Robert Bain; Ajay Vora; David R. Bentley; Mark T. Ross; Anthony V. Moorman; Christine J. Harrison

doi:10.1038/s41375-022-01799-4

Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

Claire Schwab, Ruth E. Cranston, Sarra L. Ryan, Ellie Butler, Emily Winterman, Zoe Hawking, Matthew Bashton, Amir Enshaei, Lisa J. Russell, Zoya Kingsbury, John F. Peden, Emilio Barretta, James Murray, Jude Gibson, Andrew C. Hinchliffe, Robert Bain, Ajay Vora, David R. Bentley, Mark T. Ross, Anthony V. MoormanChristine J. Harrison^*

^*Corresponding author for this work

Applied Sciences Department

Research output: Contribution to journal › Article › peer-review

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Abstract

Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

Original language	English
Pages (from-to)	529–538
Number of pages	10
Journal	Leukemia
Volume	37
Issue number	3
Early online date	22 Dec 2022
DOIs	https://doi.org/10.1038/s41375-022-01799-4
Publication status	Published - 1 Mar 2023

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Schwab, C., Cranston, R. E., Ryan, S. L., Butler, E., Winterman, E., Hawking, Z., Bashton, M., Enshaei, A., Russell, L. J., Kingsbury, Z., Peden, J. F., Barretta, E., Murray, J., Gibson, J., Hinchliffe, A. C., Bain, R., Vora, A., Bentley, D. R., Ross, M. T., ... Harrison, C. J. (2023). Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial. Leukemia, 37(3), 529–538. https://doi.org/10.1038/s41375-022-01799-4

@article{9abc943d875e4ded931169fd52a99a25,

title = "Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial",

abstract = "Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.",

author = "Claire Schwab and Cranston, {Ruth E.} and Ryan, {Sarra L.} and Ellie Butler and Emily Winterman and Zoe Hawking and Matthew Bashton and Amir Enshaei and Russell, {Lisa J.} and Zoya Kingsbury and Peden, {John F.} and Emilio Barretta and James Murray and Jude Gibson and Hinchliffe, {Andrew C.} and Robert Bain and Ajay Vora and Bentley, {David R.} and Ross, {Mark T.} and Moorman, {Anthony V.} and Harrison, {Christine J.}",

note = "Funding information: This work was funded by the Blood Cancer UK programme grant - 15036.",

year = "2023",

month = mar,

day = "1",

doi = "10.1038/s41375-022-01799-4",

language = "English",

volume = "37",

pages = "529–538",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "3",

}

Schwab, C, Cranston, RE, Ryan, SL, Butler, E, Winterman, E, Hawking, Z, Bashton, M, Enshaei, A, Russell, LJ, Kingsbury, Z, Peden, JF, Barretta, E, Murray, J, Gibson, J, Hinchliffe, AC, Bain, R, Vora, A, Bentley, DR, Ross, MT, Moorman, AV & Harrison, CJ 2023, 'Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial', Leukemia, vol. 37, no. 3, pp. 529–538. https://doi.org/10.1038/s41375-022-01799-4

TY - JOUR

T1 - Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

AU - Schwab, Claire

AU - Cranston, Ruth E.

AU - Ryan, Sarra L.

AU - Butler, Ellie

AU - Winterman, Emily

AU - Hawking, Zoe

AU - Bashton, Matthew

AU - Enshaei, Amir

AU - Russell, Lisa J.

AU - Kingsbury, Zoya

AU - Peden, John F.

AU - Barretta, Emilio

AU - Murray, James

AU - Gibson, Jude

AU - Hinchliffe, Andrew C.

AU - Bain, Robert

AU - Vora, Ajay

AU - Bentley, David R.

AU - Ross, Mark T.

AU - Moorman, Anthony V.

AU - Harrison, Christine J.

N1 - Funding information: This work was funded by the Blood Cancer UK programme grant - 15036.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

AB - Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

U2 - 10.1038/s41375-022-01799-4

DO - 10.1038/s41375-022-01799-4

M3 - Article

C2 - 36550215

SN - 0887-6924

VL - 37

SP - 529

EP - 538

JO - Leukemia

JF - Leukemia

IS - 3

ER -

Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

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