title: Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia.
abstract: Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: Ferran
authors.identifier: 0000-0003-2910-9440
authors.initials: F
authors.lastname: Nadeu
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Julio
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: Cristina
authors.initials: C
authors.lastname: Royo
authors.affiliation: Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Tycho
authors.initials: T
authors.lastname: Baumann
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: Unitat de Genòmica, IDIBAPS, Barcelona, Spain;
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Martín-García
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Ceri
authors.initials: C
authors.lastname: Oldreive
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Unitat de Genòmica, IDIBAPS, Barcelona, Spain;
authors.forename: Helena
authors.initials: H
authors.lastname: Suárez-Cisneros
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Maria
authors.initials: M
authors.lastname: Rozman
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Biología Molecular e Histocompatibilidad, Hospital Universitario, Salamanca, Spain;
authors.forename: Marcos
authors.initials: M
authors.lastname: González
authors.affiliation: Biología Molecular e Histocompatibilidad, Hospital Universitario, Salamanca, Spain;
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcoceba
authors.affiliation: Unidad de Hematología, Hospital Clínico Universitario, Valencia, Spain;
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Terol
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias, Oviedo, Spain;
authors.forename: Enrique
authors.initials: E
authors.lastname: Colado
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; and.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; and.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Unitat de Genòmica, IDIBAPS, Barcelona, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.affiliation: Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematology Department, Hospital Clínic, Barcelona, Spain; Departament d'Anatomia Patològica, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Elías
authors.identifier: 0000-0001-9850-9793
authors.initials: E
authors.lastname: Campo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000502:physiology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002999:Clone Cells; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D016158:Genes, p53; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000502:physiology; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D014411:Neoplastic Stem Cells; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000502:physiology; D051881:Receptor, Notch1 / Q000235:genetics* / Q000502:physiology; D061665:Time-to-Treatment; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
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