Molecular profiling of diffuse large B-cell lymphoma reveals a novel disease subtype with brisk host inflammatory response and distinct genetic features

Blood, 1 March 2005, Vol. 105, No. 5, pp. 1851-1861. Published: 2005.02.28

Stefano Monti, Kerry J. Savage, Jeffery L. Kutok, Friedrich Feuerhake, Paul Kurtin, Martin Mihm, Bingyan Wu, Laura Pasqualucci, Donna Neuberg, Ricardo C.T. Aguiar, Paola Dal Cin, Christine Ladd, Geraldine S. Pinkus, Gilles Salles, Nancy L. Harris, Riccardo Dalla-Favera, Thomas Habermann, Jon C. Aster, Todd R. Golub, Margaret A. Shipp

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. To identify robust and highly reproducible DLBCL subtypes with comprehensive transcriptional signatures, we utilized a large series of newly diagnosed DLBCLs, whole genome arrays and multiple clustering methods. Tumors were also analyzed for known common genetic abnormalities in DLBCL. Three discrete subsets of DLBCLs -- Oxidative Phosphorylation, B-cell Receptor/Proliferation, and Host Response (HR)-- were identified, characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/NK-cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cell markers and inflammatory mediators. HR DLBCLs also contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/GILT+/CD1a-/CD123- dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-richBCL, including fewer genetic abnormalities, younger age at presentation and frequent splenic and bone marrow involvement. These studies identify tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets.

Keywords: clusters gene expression lymphoma profiling

Supplemental Data

Description Link/Filename
Manuscript DLBCL_manuscript.pdf
Blood Highlight http://www.bloodjournal.org/cgi/content/full/105/5/1843?etoc
Figures DLBCL_manuscript.ppt
Raw '.cel' files http://www.broad.mit.edu/cgi-bin/cancer/publications/pub_paper.cgi?mode=view&paper_id=94
References DLBCL_manuscript.enl
Supplementary Information DLBCL_supplement.pdf
Raw data (mean scaled, see supplement) LF_ms_dlbcl_new_womedia.res.gz
Raw data (unscaled) LF_dlbcl_new_womedia.res.gz
Sample annotation sample_annotation.xls
2118 genes (Top 5% by F statistic) genelist.50mean.fstat95.txt
4246 genes (Top 10% by F statistic) genelist.50mean.fstat90.txt
ASH meeting presentation (slides) ASH04.pdf
ASH meeting presentation (handouts) ASH04handouts.pdf
UNIGENE and GenBank annotation of Affymetrix Affy2UnigeneGenBank.xls
UNIGENE and GenBank annotation of Lymphochip Lymphochip2UnigeneGenBank.xls
Lymphochip 2 Affymetrix mapping Lymphochip2Affy.xls
Consensus Clusters' Markers LF_ms_dlbcl_new_womedia_fstat95.DB2.unique.xls