title: Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage.
abstract: We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Queirós
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Renée
authors.initials: R
authors.lastname: Beekman
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Vilarrasa-Blasi
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Martí
authors.initials: M
authors.lastname: Duran-Ferrer
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08028, Spain.
authors.forename: Angelika
authors.initials: A
authors.lastname: Merkel
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08028, Spain.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Raineri
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Russiñol
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Kulis
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Verdaguer-Dot
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Unidad de Genómica, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.affiliation: Unidad de Genómica, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.affiliation: Department of Genetics, University of Navarra, Pamplona 31008, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University, Kiel 24105, Germany; Department of Pediatrics, Christian-Albrechts University & University Hospital Schleswig-Holstein, Kiel 24105, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University, Kiel 24105, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverría
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam 3015 CN, the Netherlands; Cancer Computational Biology Center, Erasmus MC, Rotterdam 3015 CN, the Netherlands; Department of Urology, Erasmus MC, Rotterdam 3015 CN, the Netherlands.
authors.forename: Harmen J G
authors.initials: HJG
authors.lastname: van de Werken
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Avik
authors.initials: A
authors.lastname: Datta
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Joint Program on Computational Biology, Barcelona Supercomputing Center (BSC) and Institute of Research in Biomedicine (IRB), Barcelona Science Park, Barcelona 08034, Spain.
authors.forename: Romina
authors.initials: R
authors.lastname: Royo
authors.affiliation: Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen 6500 HB, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Martens
authors.affiliation: Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Giné
authors.affiliation: Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: Lopez-Guillermo
authors.affiliation: Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen 6500 HB, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Hematopathology Section and Lymph Node Registry, Christian-Albrecht University, Kiel 24105, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Second Medical Department, University Hospital Schleswig-Holstein, Kiel 24116, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08028, Spain.
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08028, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University, Kiel 24105, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain; Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Barcelona 08036, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain. Electronic address: imartins@clinic.ub.es.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D003198:Computer Simulation; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D055751:SOXC Transcription Factors / Q000235:genetics
chemical_list: C097473:SOX11 protein, human; D055751:SOXC Transcription Factors
keywords: ChIP-seq; DNA looping; DNA methylation; SOX11; chromatin; enhancer; epigenomics; lymphoma; mantle cell lymphoma; whole-genome bisulfite sequencing