Refining diffuse large B-cell lymphoma subgroups using integrated analysis of molecular profiles

Abstract

BackgroundGene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes.Methods223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed.FindingsICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes.InterpretationThe results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups.

Transcriptome profiling reveals an integrated mRNA–lncRNA signature with predictive value for long-term survival in diffuse large B-cell lymphoma

“…Studies were included if they met the following criteria: (i) patients were newly diagnosed with primary DLBCL; (ii) gene expression profiling were conducted in pretreatment tumor tissue using the Affymetrix HU133 Plus 2.0 microarray (HG-U133 Plus_2.0); and (iii) the IPI and overall survival information were available. Five datasets were selected, GSE10846 [ 18 ], GSE31312 [ 62 ], GSE23501 [ 63 ], GSE87371 [ 64 ], and GSE98588 [ 65 ]. The selection process is illustrated in Supplementary Figure 1 .…”

c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study

“…Gene copy number aberrations were identified by performing Comparative Genomic Hybridization (CGH) on 180 patients after whole-genome amplification, using Agilent SurePrint G3 4 × 180 K microarrays, and analysis was done with GISTIC version 2.0.22 as previously described (19). Genomic imbalance complexity was calculated as the number of all gene loci for which the GISTIC score was −2 (homozygous deletion) or +2 (copy number gain of 2+ copies).…”

“…Fluorescence in situ hybridization (FISH) for BCL2, BCL6, and MYC translocations was performed as previously detailed (19). Probes are listed in the Supplementary Materials and Methods.…”

“…The Lymphopanel was designed to identify mutations in 34 important lymphomagenesis genes as detailed previously (19). NGS data was available for 213 patients.…”

Twenty years later: has cell of origin testing in diffuse large B cell lymphoma run its course?

“…Three recent studies that focused on the mutational landscape of DLBCLs have identified high-risk mutational profiles among DLBCLs, some of which appear COOindependent [23][24][25]. Their findings provide a rationale for targeted therapies, such as one that used clinical data in concert with DNA and gene expression analysis to identify a high-risk subgroup of patients with non-GCB DLBCLs who benefit from the addition of lenalidomide to R-CHOP [26].…”