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Cancer Cell. 2016 Nov 14;30(5):806-821. doi: 10.1016/j.ccell.2016.09.014.

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage.

Author information

1
Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain.
2
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
3
Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08028, Spain.
4
Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
5
Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona 08036, Spain; Unidad de Genómica, IDIBAPS, Barcelona 08036, Spain.
6
Unidad de Genómica, IDIBAPS, Barcelona 08036, Spain.
7
Department of Genetics, University of Navarra, Pamplona 31008, Spain.
8
Institute of Human Genetics, Christian-Albrechts University, Kiel 24105, Germany; Department of Pediatrics, Christian-Albrechts University & University Hospital Schleswig-Holstein, Kiel 24105, Germany.
9
Institute of Human Genetics, Christian-Albrechts University, Kiel 24105, Germany.
10
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.
11
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
12
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
13
Joint Program on Computational Biology, Barcelona Supercomputing Center (BSC) and Institute of Research in Biomedicine (IRB), Barcelona Science Park, Barcelona 08034, Spain.
14
Molecular Biology, NCMLS, FNWI, Radboud University, Nijmegen 6500 HB, the Netherlands.
15
Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain.
16
Hematopathology Section and Lymph Node Registry, Christian-Albrecht University, Kiel 24105, Germany.
17
Second Medical Department, University Hospital Schleswig-Holstein, Kiel 24116, Germany.
18
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.
19
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.

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.

KEYWORDS:

ChIP-seq; DNA looping; DNA methylation; SOX11; chromatin; enhancer; epigenomics; lymphoma; mantle cell lymphoma; whole-genome bisulfite sequencing

PMID:
27846393
PMCID:
PMC5805090
DOI:
10.1016/j.ccell.2016.09.014
[Indexed for MEDLINE]
Free PMC Article

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