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

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

doi:10.1038/s41375-020-0723-2

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

Stuart J. Blakemore, Ruth Clifford, Helen Parker, Pavlos Antoniou, Ewa Stec-Dziedzic, Marta Larrayoz, Zadie Davis, Latha Kadalyayil, Andrew Colins, Pauline Robbe, Dimitris Vavoulis, Jade Forster, Louise Carr, Ricardo Morilla, Monica Else, Dean Bryant, Helen McCarthy, Renata J. Walewska, Andrew J. Steele, Jacqueline ChanGraham Speight, Tanja Stankovic, Mark S. Cragg, Daniel Catovsky, David G. Oscier, Matthew J.J. Rose-Zerilli, Anna Schuh, Jonathan C. Strefford^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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

26 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1760-1774
Number of pages	15
Journal	Leukemia
Volume	34
Issue number	7
DOIs	https://doi.org/10.1038/s41375-020-0723-2
Publication status	Published - 1 Jul 2020

Bibliographical note

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).

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

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

Access to Document

10.1038/s41375-020-0723-2

Cite this

Blakemore, S. J., Clifford, R., Parker, H., Antoniou, P., Stec-Dziedzic, E., Larrayoz, M., Davis, Z., Kadalyayil, L., Colins, A., Robbe, P., Vavoulis, D., Forster, J., Carr, L., Morilla, R., Else, M., Bryant, D., McCarthy, H., Walewska, R. J., Steele, A. J., ... Strefford, J. C. (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. https://doi.org/10.1038/s41375-020-0723-2

@article{998d9672df03473fa1bd38019b33ca34,

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

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.",

author = "Blakemore, {Stuart J.} and Ruth Clifford and Helen Parker and Pavlos Antoniou and Ewa Stec-Dziedzic and Marta Larrayoz and Zadie Davis and Latha Kadalyayil and Andrew Colins and Pauline Robbe and Dimitris Vavoulis and Jade Forster and Louise Carr and Ricardo Morilla and Monica Else and Dean Bryant and Helen McCarthy and Walewska, {Renata J.} and Steele, {Andrew J.} and Jacqueline Chan and Graham Speight and Tanja Stankovic and Cragg, {Mark S.} and Daniel Catovsky and Oscier, {David G.} and Rose-Zerilli, {Matthew J.J.} and Anna Schuh and Strefford, {Jonathan C.}",

note = "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{\textquoteright}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: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = jul,

day = "1",

doi = "10.1038/s41375-020-0723-2",

language = "English",

volume = "34",

pages = "1760--1774",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "7",

}

Blakemore, SJ, Clifford, R, Parker, H, Antoniou, P, Stec-Dziedzic, E, Larrayoz, M, Davis, Z, Kadalyayil, L, Colins, A, Robbe, P, Vavoulis, D, Forster, J, Carr, L, Morilla, R, Else, M, Bryant, D, McCarthy, H, Walewska, RJ, Steele, AJ, Chan, J, Speight, G, Stankovic, T, Cragg, MS, Catovsky, D, Oscier, DG, Rose-Zerilli, MJJ, Schuh, A & Strefford, JC 2020, 'Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial', Leukemia, vol. 34, no. 7, pp. 1760-1774. https://doi.org/10.1038/s41375-020-0723-2

TY - JOUR

T1 - Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia

T2 - data from the randomised UK LRF CLL4 trial

AU - Blakemore, Stuart J.

AU - Clifford, Ruth

AU - Parker, Helen

AU - Antoniou, Pavlos

AU - Stec-Dziedzic, Ewa

AU - Larrayoz, Marta

AU - Davis, Zadie

AU - Kadalyayil, Latha

AU - Colins, Andrew

AU - Robbe, Pauline

AU - Vavoulis, Dimitris

AU - Forster, Jade

AU - Carr, Louise

AU - Morilla, Ricardo

AU - Else, Monica

AU - Bryant, Dean

AU - McCarthy, Helen

AU - Walewska, Renata J.

AU - Steele, Andrew J.

AU - Chan, Jacqueline

AU - Speight, Graham

AU - Stankovic, Tanja

AU - Cragg, Mark S.

AU - Catovsky, Daniel

AU - Oscier, David G.

AU - Rose-Zerilli, Matthew J.J.

AU - Schuh, Anna

AU - Strefford, Jonathan C.

N1 - 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).

PY - 2020/7/1

Y1 - 2020/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85078950621&partnerID=8YFLogxK

U2 - 10.1038/s41375-020-0723-2

DO - 10.1038/s41375-020-0723-2

M3 - Article

C2 - 32015491

AN - SCOPUS:85078950621

SN - 0887-6924

VL - 34

SP - 1760

EP - 1774

JO - Leukemia

JF - Leukemia

IS - 7

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this