Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase-mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.next-generation sequencing | human genetics | activation-induced deaminase D iffuse large B-cell lymphoma (DLBCL) is an aggressive nonHodgkin lymphoma that affects 30,000 new patients in the United States every year (1, 2). The standard of care for the treatment of most cases of DLBCL is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) consisting of multiagent chemotherapy plus a therapeutic antibody directed against CD20, a marker of B lymphocytes. The 3-year event-free survival rate is approximately 60%, with the majority of the remaining 40% dying of their disease (3). To date, treatment strategies to improve outcome have largely included increased doses of standard agents in the context of autologous stem cell transplantation (4). Therefore, there is a great medical need to define the genetic abnormalities that are associated with DLBCL to define novel targets for therapy.Germinal centers (GCs) in lymphoid tissues are sites of clonal expansion and editing of the Ig receptor in B lymphocytes, and this GC reaction is a physiological component of the humoral immune response. Somatic hypermutation (SHM) is part of the GC reaction, and its dysregulation contributes to the accumulation of somatic mutations in oncogenes and tumor-suppressor genes in B lymphocytes.Traditionally, DLBCL has been classified by the morphology and immunophenotype of the malignant B-cells but more recently, molecular classifications have been reported. Specifically, gene expression-based classification o...

Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely unde-

Since their discovery in 1998, the two TNF family members APRIL and BLyS/BAFF have received increasing attention. In addition to regulating normal B-cell development and immune responses, these molecules might be crucial in a diverse set of diseases, including autoimmunity and cancer. Although more has been published about the general biology of BLyS/BAFF than that of APRIL, many recent articles have described novel APRIL biology. Here we focus on APRIL, exploring its normal and pathological functions, and comparing the therapeutic molecules currently under development that target BLyS/BAFF alone, or APRIL and BLyS/BAFF together.