title: Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.
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 DL-BCL subtypes with comprehensive transcriptional signatures, we used 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. There were 3 discrete subsets of DLBCL-"oxidative phosphorylation," "B-cell receptor/proliferation," and "host response" (HR)-identified characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/natural killer cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cell markers, and inflammatory mediators. HR DLB-CLs also contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/gamma interferon-induced lysosomal transferase-positive (GILT+) CD1a-/CD123- dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, 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.
authors.affiliation: The Broad Institute, Cambridge, MA, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Friedrich
authors.initials: F
authors.lastname: Feuerhake
authors.forename: Paul
authors.initials: P
authors.lastname: Kurtin
authors.forename: Martin
authors.initials: M
authors.lastname: Mihm
authors.forename: Bingyan
authors.initials: B
authors.lastname: Wu
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Christine
authors.initials: C
authors.lastname: Ladd
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Nancy Lee
authors.initials: NL
authors.lastname: Harris
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007109:Immunity / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D011947:Receptors, Antigen, B-Cell