Relapsed diffuse large B-cell lymphoma present different genomic patterns of alterations between early and late relapses. Homo sapiens

Despite major advances in first-line treatment, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will experience treatment failure. Time of relapse is a major prognostic parameter in this context, with a particularly poor prognosis for early relapse. Our purpose was to determine genomic alterations associated with early-relapsed (ER) and late-relapsed (LR) DLBCLs, using high resolution array-based comparative genomic hybridization and integrating structural abnormalities and gene expression of 39 samples from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study. ER and LR DLBCLs present a similar landscape of large copy number variations (CNVs), with an average 14.89 and 16.11 CNVs per sample, respectively (p=0.81). Deletions of CDKN2A/B (28%) and IBTK (23%) were frequent events in relapsed DLBCLs. We identified 56 protein-coding genes and 25 long non-coding RNAs with significantly differential CNVs distribution between ER and LR DLBCLs with a false discovery rate < 0.05. In ER DLBCLs, genetic abnormalities were related to regulation of transcription, cell cycle and apoptosis, with duplications of histone H1T (31%), deletions of DIABLO (26%), PTMS (21%) and CK2B (15%). In LR DLBCLs, genetic aberrations were related to immune response, with alterations of IgHV (40%), IgKV (15%), and deletions of B2M (20%) and CD58 (10%), regulation of cell proliferation, with duplications of HES1 and DVL3 (25% and 20%, respectively) and regulation of transcription, with MTERF4 deletions (20%). This study provides new insights into the genetic abnormalities in relapsed DLBCLs. Dysregulation of cell cycle, apoptosis and gene transcription may indicate targeted therapy. Overall design: Comparative study of CNVs in 19 early- and 20 late-relapsed DLBCLs