Chromosomal Imbalances in Germinal Center B-Cell-Like and Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Influence Gene Expression Signatures and Improve Gene Expression-Based Survival Prediction(the First Two Authors Contributed Equally to This Work).

Introduction: Germinal center B-cell (GCB)-like and activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL) are characterized by different recurrent chromosomal imbalances. In a series of 177 untreated de novo DLBCL analyzed by comparative genomic hybridization (CGH), GCB-like DLBCL had shown more frequent gains of chromosome 12p/12cen-q14 (22% vs 5%, p=.0025), whereas ABC-like DLBCL had shown more frequent gains of 3/3q27-qter (34% vs 6%; p<0.0001), 18q21 (36% vs 11%;p=0.0002) and losses of 6q21-q23 (36% vs 20%; p=0.0269). We investigated the impact of chromosomal imbalances on the transcription of genes localized in the corresponding chromosomal regions, and on gene expression signatures, as previously defined (

Results: Gains/amplifications of chromosomes 2p, 3q, 12q and 18q resulted in different gene expression patterns depending on the array-defined DLBCL subtype. For example, 18q gains/amplifications correlated with overexpression of P15RS, MADH2, MADH4, LOC51320 and PMAIP1 in GCB-like DLBCL, whereas P15RS, MIZ1, MADH2, ME2, MADH4, LOC51320, MALT1, PMAIP1, BCL2, FVT1 and NFATC1 were overexpressed in ABC-like DLBCL with 18q gains/amplifications (p<0.05). Chromosomal imbalances also were strongly associated with certain alterations of gene expression signatures. Gains of chromosome 7 in GCB-like DLBCL, losses of chromosome 17p13 in ABC-like DLBCL, and gains of chromosome 12 both in GCB- and ABC-like DLBCL resulted in a loss of the T-cell signature (p<0.001). Similarily, ABC-like DLBCL with gains of chromosome 3q but not Xp, or gains of 8q showed a loss of the lymph node signature, whereas ABC-like DLBCL with gains of Xp but not 3q showed a strong lymph node signature (p<0.001). Importantly, chromosomal imbalances were identified (gains of Xp, 3p, and losses of 6q13) that significantly improved the previously-defined gene expression-based outcome predictor for DLBCL patients (Rosenwald et al., NEJM, 2002).

Conclusion: In GCB-like and ABC-like DLBCL, chromosomal imbalances lead to subgroup-specific overexpression of genes located within the gained/amplified regions. Chromosomal imbalances furthermore are associated with profound changes in the gene expression signatures in both GCB- and ABC-like DLBCL. Importantly, consideration of chromosomal imbalances significantly improves on the previously-defined gene expression based outcome predictors for DLBCL patients.