Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma

Alexander M. Newman; Masood Zaka; Peixun Zhou; Alex E. Blain; Amy Erhorn; Amy Barnard; Rachel E. Crossland; Sarah Wilkinson; Amir Enshaei; Julian De Zordi; Fiona Harding; Mary Taj; Katrina M. Wood; Despina Televantou; Suzanne D. Turner; G. A.Amos Burke; Christine J. Harrison; Simon Bomken; Chris M. Bacon; Vikki Rand

doi:10.1038/s41375-021-01444-6

Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma

Alexander M. Newman, Masood Zaka, Peixun Zhou, Alex E. Blain, Amy Erhorn, Amy Barnard, Rachel E. Crossland, Sarah Wilkinson, Amir Enshaei, Julian De Zordi, Fiona Harding, Mary Taj, Katrina M. Wood, Despina Televantou, Suzanne D. Turner, G. A.Amos Burke, Christine J. Harrison, Simon Bomken, Chris M. Bacon, Vikki Rand^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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Abstract

Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

Original language	English
Pages (from-to)	781-789
Number of pages	9
Journal	Leukemia
Volume	36
Issue number	3
Early online date	21 Oct 2021
DOIs	https://doi.org/10.1038/s41375-021-01444-6
Publication status	Published - Mar 2022

Bibliographical note

Funding Information:
This study was supported by a Blood Cancer UK Senior Bennett Fellowship (#12005), the Newcastle upon Tyne Hospitals NHS Charity, North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, the Little Princess Trust, the North of England Children’s Cancer Research Fund (NECCR), the Good Will Cause, the Hannah Bloom Charitable Trust, Cancer Research North East, the National Institute for Health Research (NIHR) Newcastle In Vitro Diagnostics Co-operative, the MRC/EPSRC Newcastle Molecular Pathology Node (NovoPath) and MRC Clinician Scientist Fellowship (MR/S021590/1). We thank all the patients, clinicians and staff who participated in the collection of material and clinical data at the Children’s Cancer and Leukaemia Group (CCLG) Tissue Bank. The CCLG Tissue Bank is funded by Cancer Research UK.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Newman, A. M., Zaka, M., Zhou, P., Blain, A. E., Erhorn, A., Barnard, A., Crossland, R. E., Wilkinson, S., Enshaei, A., De Zordi, J., Harding, F., Taj, M., Wood, K. M., Televantou, D., Turner, S. D., Burke, G. A. A., Harrison, C. J., Bomken, S., Bacon, C. M., & Rand, V. (2022). Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma. Leukemia, 36(3), 781-789. https://doi.org/10.1038/s41375-021-01444-6

@article{376875c2f4074c60b931139ff1ff2b05,

title = "Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma",

abstract = "Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.",

author = "Newman, {Alexander M.} and Masood Zaka and Peixun Zhou and Blain, {Alex E.} and Amy Erhorn and Amy Barnard and Crossland, {Rachel E.} and Sarah Wilkinson and Amir Enshaei and {De Zordi}, Julian and Fiona Harding and Mary Taj and Wood, {Katrina M.} and Despina Televantou and Turner, {Suzanne D.} and Burke, {G. A.Amos} and Harrison, {Christine J.} and Simon Bomken and Bacon, {Chris M.} and Vikki Rand",

note = "Funding Information: This study was supported by a Blood Cancer UK Senior Bennett Fellowship (#12005), the Newcastle upon Tyne Hospitals NHS Charity, North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, the Little Princess Trust, the North of England Children{\textquoteright}s Cancer Research Fund (NECCR), the Good Will Cause, the Hannah Bloom Charitable Trust, Cancer Research North East, the National Institute for Health Research (NIHR) Newcastle In Vitro Diagnostics Co-operative, the MRC/EPSRC Newcastle Molecular Pathology Node (NovoPath) and MRC Clinician Scientist Fellowship (MR/S021590/1). We thank all the patients, clinicians and staff who participated in the collection of material and clinical data at the Children{\textquoteright}s Cancer and Leukaemia Group (CCLG) Tissue Bank. The CCLG Tissue Bank is funded by Cancer Research UK. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41375-021-01444-6",

language = "English",

volume = "36",

pages = "781--789",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "3",

}

Newman, AM, Zaka, M, Zhou, P, Blain, AE, Erhorn, A, Barnard, A, Crossland, RE, Wilkinson, S, Enshaei, A, De Zordi, J, Harding, F, Taj, M, Wood, KM, Televantou, D, Turner, SD, Burke, GAA, Harrison, CJ, Bomken, S, Bacon, CM & Rand, V 2022, 'Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma', Leukemia, vol. 36, no. 3, pp. 781-789. https://doi.org/10.1038/s41375-021-01444-6

TY - JOUR

T1 - Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma

AU - Newman, Alexander M.

AU - Zaka, Masood

AU - Zhou, Peixun

AU - Blain, Alex E.

AU - Erhorn, Amy

AU - Barnard, Amy

AU - Crossland, Rachel E.

AU - Wilkinson, Sarah

AU - Enshaei, Amir

AU - De Zordi, Julian

AU - Harding, Fiona

AU - Taj, Mary

AU - Wood, Katrina M.

AU - Televantou, Despina

AU - Turner, Suzanne D.

AU - Burke, G. A.Amos

AU - Harrison, Christine J.

AU - Bomken, Simon

AU - Bacon, Chris M.

AU - Rand, Vikki

N1 - Funding Information: This study was supported by a Blood Cancer UK Senior Bennett Fellowship (#12005), the Newcastle upon Tyne Hospitals NHS Charity, North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, the Little Princess Trust, the North of England Children’s Cancer Research Fund (NECCR), the Good Will Cause, the Hannah Bloom Charitable Trust, Cancer Research North East, the National Institute for Health Research (NIHR) Newcastle In Vitro Diagnostics Co-operative, the MRC/EPSRC Newcastle Molecular Pathology Node (NovoPath) and MRC Clinician Scientist Fellowship (MR/S021590/1). We thank all the patients, clinicians and staff who participated in the collection of material and clinical data at the Children’s Cancer and Leukaemia Group (CCLG) Tissue Bank. The CCLG Tissue Bank is funded by Cancer Research UK. Publisher Copyright: © 2021, The Author(s).

PY - 2022/3

Y1 - 2022/3

N2 - Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

AB - Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

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ER -

Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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