Identification of genes putatively involved in the pathogenesis of diffuse large B-cell lymphomas by integrative genomics.

Diffuse large B-cell lymphomas (DLBCL) are highly heterogeneous with regard to clinical presentation and outcome. DLBCL copy number aberrations have been identified previously, of which the deletion at 6q21-24 was significantly associated with a highly favorable clinical response to chemotherapy. In this study, we aimed to identify genes implicated in this and other genomic regions with recurrent losses and/or gains. To identify implicated genes, we superimposed array comparative genomic hybridization (aCGH) data onto a microarray expression dataset of 42 clinically well-characterized primary nodal DLBCL biopsies. We confirmed that loss of 6q21-24 is significantly associated with a highly favorable clinical response to chemotherapy. Our approach identified 316 significant genes restricted to 32 chromosomal regions, including 24 genes identified at 6q21-24. In an independent dataset, 18% of overexpressed genes in gained regions and 55% of down-regulated genes in deleted regions were validated. In summary, using integrative genomics novel onco and tumor suppressor genes were identified in DLBCL that were not recognized by expression profiling alone.