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

Antineoplastic Combined Chemotherapy Protocols / therapeutic use Ataxia Telangiectasia Mutated Proteins / genetics Baculoviral IAP Repeat-Containing 3 Protein / genetics Biomarkers, Tumor / genetics Cohort Studies Cyclophosphamide / administration & dosage Extracellular Signal-Regulated MAP Kinases / genetics Follow-Up Studies Gene Expression Regulation, Neoplastic Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy MAP Kinase Signaling System / genetics Mutation Prognosis Survival Rate Tumor Suppressor Protein p53 / genetics Vidarabine / administration & dosage

Journal

Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895

Informations de publication

Date de publication:
07 2020
Historique:
received: 25 07 2019
accepted: 22 01 2020
revised: 06 12 2019
pubmed: 6 2 2020
medline: 28 10 2020
entrez: 5 2 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41375-020-0723-2 PMID: 32015491 PMC: PMC7326706
pubmed: 32015491
doi: 10.1038/s41375-020-0723-2
pii: 10.1038/s41375-020-0723-2
pmc: PMC7326706
mid: EMS85579
doi:

Substances chimiques

Biomarkers, Tumor 0
TP53 protein, human 0
Tumor Suppressor Protein p53 0
Cyclophosphamide 8N3DW7272P
BIRC3 protein, human EC 2.3.2.27
Baculoviral IAP Repeat-Containing 3 Protein EC 2.3.2.27
ATM protein, human EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1
Extracellular Signal-Regulated MAP Kinases EC 2.7.11.24
Vidarabine FA2DM6879K
fludarabine P2K93U8740

Types de publication

Clinical Trial, Phase III Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1760-1774

Subventions

Organisme : Cancer Research UK
ID : A15581
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A18087
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A23669
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom

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Auteurs

Stuart J Blakemore (SJ)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Department I of Internal Medicine, Centre of Excellence in Aging Research, University of Cologne, Cologne, Germany.

Ruth Clifford (R)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.

Helen Parker (H)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Pavlos Antoniou (P)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.

Ewa Stec-Dziedzic (E)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.

Marta Larrayoz (M)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Zadie Davis (Z)

Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.

Latha Kadalyayil (L)

Genetic Epidemiology and Bioinformatics, Faculty of Medicine, University of Southampton, Southampton, UK.

Andrew Colins (A)

Genetic Epidemiology and Bioinformatics, Faculty of Medicine, University of Southampton, Southampton, UK.
ORCID: 0000-0001-7108-0771

Pauline Robbe (P)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.

Dimitris Vavoulis (D)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
ORCID: 0000-0002-3984-1507

Jade Forster (J)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Louise Carr (L)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Ricardo Morilla (R)

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Monica Else (M)

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Dean Bryant (D)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Helen McCarthy (H)

Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.

Renata J Walewska (RJ)

Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.

Andrew J Steele (AJ)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
ORCID: 0000-0003-0667-1596

Jacqueline Chan (J)

Oxford Gene Technology, Begbroke Science Park, Begbroke, Oxfordshire, UK.

Graham Speight (G)

Oxford Gene Technology, Begbroke Science Park, Begbroke, Oxfordshire, UK.

Tanja Stankovic (T)

Institute of Cancer and Genomic Sciences, College of Medical and Dental Services, IBR West, University of Birmingham, Birmingham, UK.

Mark S Cragg (MS)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Antibody & Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

Daniel Catovsky (D)

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

David G Oscier (DG)

Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.

Matthew J J Rose-Zerilli (MJJ)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Anna Schuh (A)

Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.

Jonathan C Strefford (JC)

Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. jcs@soton.ac.uk.
ORCID: 0000-0002-0972-2881

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Classifications MeSH

questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Protéines mutées dans l'ataxie-télangiectasie › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Protéines IAP › Protéine-3 contenant des répétitions IAP baculovirales › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Composés chimiques organiques › Composés organiques du phosphore › Phosphoramides › Moutardes phosphoramide › Cyclophosphamide › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Mitogen-Activated Protein Kinases › Extracellular Signal-Regulated MAP Kinases › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études de suivi › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › Clinical significance of TP53, BIRC3, ATM and...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Clinical significance of TP53, BIRC3, ATM and...
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