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Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial
Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

0887-6924
1760-1774
Blakemore, Stuart J.
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Clifford, Ruth
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Davis, Zadie
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Stankovic, Tanja
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Cragg, Mark S.
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Catovsky, Daniel
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Blakemore, Stuart J.
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Clifford, Ruth
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McCarthy, Helen
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Walewska, Renata J.
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Stankovic, Tanja
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Cragg, Mark S.
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Catovsky, Daniel
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Oscier, David G.
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Rose-Zerilli, Matthew J.J.
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Blakemore, Stuart J., Clifford, Ruth, Parker, Helen, Antoniou, Pavlos, Stec-Dziedzic, Ewa, Larrayoz, Marta, Davis, Zadie, Kadalyayil, Latha, Collins, Andrew, Robbe, Pauline, Vavoulis, Dimitris, Forster, Jade, Carr, Louise, Morilla, Ricardo, Else, Monica, Bryant, Dean, McCarthy, Helen, Walewska, Renata J., Steele, Andrew J., Chan, Jacqueline, Speight, Graham, Stankovic, Tanja, Cragg, Mark S., Catovsky, Daniel, Oscier, David G., Rose-Zerilli, Matthew J.J., Schuh, Anna and Strefford, Jon (2020) Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia, 34 (7), 1760-1774. (doi:10.1038/s41375-020-0723-2).

Record type: Article

Abstract

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

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Accepted/In Press date: 22 January 2020
e-pub ahead of print date: 3 February 2020
Published date: 1 July 2020
Additional Information: Funding Information: Acknowledgements The authors would like to gratefully acknowledge all the patients and clinicians than contributed to the UK CLL4 trial. The CLL4 trial was funded by a core grant from Bloodwise. ME was supported by the Arbib Charitable Fund. This study was supported by grants from Bloodwise (12036, 11052), Kay Kendall Leukaemia Fund (873), Cancer Research UK (C2750/A23669, C34999/A18087, ECMC C24563/A15581) and the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. Thank you to Miss Kate Latham for contributing to DNA extraction of CLL4 patient samples. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 436399
URI: http://eprints.soton.ac.uk/id/eprint/436399
ISSN: 0887-6924
PURE UUID: 448e7b88-6f47-4d09-9cb7-7eb95a7b1942
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for Jon Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 10 Dec 2019 17:30
Last modified: 16 Nov 2021 05:02

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Contributors

Author: Stuart J. Blakemore
Author: Ruth Clifford
Author: Helen Parker
Author: Pavlos Antoniou
Author: Ewa Stec-Dziedzic
Author: Marta Larrayoz
Author: Zadie Davis
Author: Latha Kadalyayil
Author: Andrew Collins ORCID iD
Author: Pauline Robbe
Author: Dimitris Vavoulis
Author: Jade Forster
Author: Louise Carr
Author: Ricardo Morilla
Author: Monica Else
Author: Dean Bryant
Author: Helen McCarthy
Author: Renata J. Walewska
Author: Andrew J. Steele
Author: Jacqueline Chan
Author: Graham Speight
Author: Tanja Stankovic
Author: Mark S. Cragg
Author: Daniel Catovsky
Author: David G. Oscier
Author: Matthew J.J. Rose-Zerilli
Author: Anna Schuh
Author: Jon Strefford ORCID iD

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