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," "Bcell 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 DLBCLs also contained significantly higher numbers of morphologically distinct CD2 ؉ /CD3 ؉ tumor-infiltrating lymphocytes and interdigitating S100 ؉ /gamma interferon-induced ly-

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

“…Monti and colleagues 24 stratified diffuse large B-cell lymphomas into three groups on the basis of their patterns of gene expression. One group, with overexpression of genes involved in B-cell differentiation or proliferation, overexpressed HSP90.…”

Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas

“…53BP1 copy loss in DLBCL subtypes Primary DLBCLs were previously assigned to one of three tumor subtypes, HR, OxPhos or BCR, on the basis of comprehensive transcriptional profiles (Monti et al, 2005). HR tumors exhibit a prominent host inflammatory/immune response and resemble T-cell/ histiocyte-rich LBCLs, whereas OxPhos tumors have increased expression of genes involved in oxidative phosphorylation and more common structural abnormalities of intrinsic and extrinsic apoptotic pathway components (Monti et al, 2005;Takahashi et al, 2006).…”

“…HR tumors exhibit a prominent host inflammatory/immune response and resemble T-cell/ histiocyte-rich LBCLs, whereas OxPhos tumors have increased expression of genes involved in oxidative phosphorylation and more common structural abnormalities of intrinsic and extrinsic apoptotic pathway components (Monti et al, 2005;Takahashi et al, 2006). In contrast, BCR DLBCLs express higher levels of multiple BCR signaling cascade components, DNAdamage response proteins such as H2AX and B-cell transcription factors including BCL6; these tumors also have more frequent BCL6 translocations (Monti et al, 2005;Takahashi et al, 2006). Recent studies also indicate that BCR DLBCLs exhibit unique reliance upon BCL6 signaling and sensitivity to BCL6 peptide inhibitors (Polo et al, 2007).…”

“…Sixty-three primary DLBCLs from a previously described series (Monti et al, 2005) had additional high-quality DNA available for analysis. Since paired normal DNAs from the DLBCL patients were unavailable, DNAs from a series of 180 normal individuals from the International HapMap Project (http://www.hapmap.org/) were used as reference samples.…”

“…Integrated analysis of transcriptional profiles and HD SNP array data Transcriptional profiling of the 63 primary DLBCLs was reported previously (Monti et al, 2005). To analyse the association between copy number abnormalities and gene transcript abundance, tumor samples were sorted into two classes, those with copy gain (or loss) and those with normal copy numbers.…”