<p>We performed massively parallel whole exome sequencing of 55 primary tumor samples from patients with diffuse large B cell lymphoma (DLBCL) and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, as well as in genes for which a functional role in DLBCL has not been previously suspected. Significantly mutated genes include <a href="https://www.ncbi.nlm.nih.gov/gene/4615">MYD88</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/84433">CARD11</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/2146">EZH2</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/1387">CREBBP</a>, as well as <a href="https://www.ncbi.nlm.nih.gov/gene/100271849">MEF2B</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/8085">MLL2</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/694">BTG1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/10672">GNA13</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/60">ACTB</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/286530">P2RY8</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/27445">PCLO</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/8764">TNFRSF14</a>. Analysis of somatic mutations in patients with DLBCL also revealed that <a href="https://www.ncbi.nlm.nih.gov/gene/596">BCL2</a> 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, likely caused by activation-induced cytidine deaminase (AID)-mediated somatic hypermutation, and those non-synonymous 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. We further identified genes with mutations that are likely to be functionally relevant despite being mutated at a low rate. These genes include <a href="https://www.ncbi.nlm.nih.gov/gene/3845">KRAS</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/673">BRAF</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/4851">NOTCH1</a> as likely drivers of DLBCL pathogenesis in some patients.</p><p>In order to facilitate additional in vitro and in vivo analyses of the discrete molecular clusters and associated targeted therapies in preclinical models, we also performed our subtyping analysis on 28 Diffuse Large B-Cell Lymphoma (DLBCL) cell lines. We performed whole exome sequencing (WES) on these cell lines to capture structural variants (SVs), from which we obtained full genetic characterization and segregation of these cell lines into our previously defined molecular clusters by DLBclass assignment. These analyses are available in an interactive <a href="https://getzlab.org/dlbcl-classifier-portal/">DLBclass portal</a> available to the public. Our data provide an unbiased view of the landscape of mutations in DLBCL. These data may point towards new targets for the treatment of DLBCL.</p>

Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma

Genomic Analyses of PMBL Reveal New Drivers and Mechanisms of Sensitivity to PD-1 Blockade.

DLBclass: A Probabilistic Molecular Classifier to Guide Clinical Investigation and Practice in DLBCL.