title: A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.
abstract: Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A C
authors.initials: AC
authors.lastname: Queirós
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Clot
authors.affiliation: Servicio de Hematología, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martinez-Trillos
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Kulis
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: E M M
authors.initials: EM
authors.lastname: Penas
authors.affiliation: MRC Toxicology Unit Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Jayne
authors.affiliation: MRC Toxicology Unit Leicester, Leicester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Majid
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: A K
authors.initials: AK
authors.lastname: Bergmann
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kolarova
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Royo
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Russiñol
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pinyol
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Bea
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rozman
authors.affiliation: Servicio de Hematología, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Servicio de Hematología, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Giné
authors.affiliation: Servicio de Hematología, Hospital Universitario, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Universidad de Salamanca, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: González-Díaz
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: X S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, Leicester University, Leicester, UK.
authors.forename: M J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: C
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Josep Carreras Leukemia Research Institute, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rozman
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.affiliation: Servicio de Hematología, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: J I
authors.initials: JI
authors.lastname: Martín-Subero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D060388:Support Vector Machine; D016019:Survival Analysis; D061665:Time-to-Treatment; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains