DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma

Rita Shaknovich, Huimin Geng, Nathalie A. Johnson, Lucas Tsikitas, Leandro Cerchietti, John M. Greally, Randy D. Gascoyne, Olivier Elemento, Ari Melnick

Research output: Contribution to journalArticle

94 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBlood
Volume116
Issue number20
DOIs
StatePublished - Nov 18 2010

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Lymphoma, Large B-Cell, Diffuse
DNA Methylation
B-Lymphocytes
Genes
Cells
Methylation
Gene expression
Epigenomics
Biomarkers
Labels
Assays
Classifiers
Tumor Necrosis Factor-alpha
Germinal Center
Gene Regulatory Networks
Gene Expression Profiling
Proteins
Phenotype
Gene Expression
Survival

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Shaknovich, R., Geng, H., Johnson, N. A., Tsikitas, L., Cerchietti, L., Greally, J. M., ... Melnick, A. (2010). DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood, 116(20). https://doi.org/10.1182/blood-2010-05-285320

DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. / Shaknovich, Rita; Geng, Huimin; Johnson, Nathalie A.; Tsikitas, Lucas; Cerchietti, Leandro; Greally, John M.; Gascoyne, Randy D.; Elemento, Olivier; Melnick, Ari.

In: Blood, Vol. 116, No. 20, 18.11.2010.

Research output: Contribution to journalArticle

Shaknovich, R, Geng, H, Johnson, NA, Tsikitas, L, Cerchietti, L, Greally, JM, Gascoyne, RD, Elemento, O & Melnick, A 2010, 'DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma', Blood, vol. 116, no. 20. https://doi.org/10.1182/blood-2010-05-285320
Shaknovich, Rita ; Geng, Huimin ; Johnson, Nathalie A. ; Tsikitas, Lucas ; Cerchietti, Leandro ; Greally, John M. ; Gascoyne, Randy D. ; Elemento, Olivier ; Melnick, Ari. / DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. In: Blood. 2010 ; Vol. 116, No. 20.
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