title: DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma.
abstract: Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell-like (GCB) and activated B cell-like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50,000 CpG motifs distributed among more than 14,000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-α signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Lucas
authors.initials: L
authors.lastname: Tsikitas
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification* / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha