title: Epigenomic evolution in diffuse large B-cell lymphomas.
abstract: The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.
authors.affiliation: 1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Pan
authors.affiliation: 1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [3] Hematology/Oncology Division, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA [2] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Boi
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA [2] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tabbò
authors.affiliation: 1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: David
authors.initials: D
authors.lastname: Redmond
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Nie
authors.affiliation: Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria 10126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ladetto
authors.affiliation: Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin 10126, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiappella
authors.affiliation: Hematology/Oncology Division, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Hematology/Oncology Division, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.affiliation: 1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Hematology/Oncology Division, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA [2] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Inghirami
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: 1] Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA [2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
mesh_terms: D005075:Biological Evolution; D019175:DNA Methylation; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D059467:Transcriptome
chemical_list: D009363:Neoplasm Proteins