Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

<jats:p> 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 <jats:italic>MYD88</jats:italic> , <jats:italic>CARD11</jats:italic> , <jats:italic>EZH2</jats:italic> , and <jats:italic>CREBBP</jats:italic> . We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include <jats:italic>MEF2B</jats:italic> , <jats:italic>MLL2</jats:italic> , <jats:italic>BTG1</jats:italic> , <jats:italic>GNA13</jats:italic> , <jats:italic>ACTB</jats:italic> , <jats:italic>P2RY8</jats:italic> , <jats:italic>PCLO</jats:italic> , and <jats:italic>TNFRSF14</jats:italic> . Further, we show that <jats:italic>BCL2</jats:italic> mutations commonly occur in patients with <jats:italic>BCL2</jats:italic> / <jats:italic>IgH</jats:italic> rearrangements as a result of somatic hypermutation normally occurring at the <jats:italic>IgH</jats:italic> locus. The <jats:italic>BCL2</jats:italic> 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 <jats:italic>BCL2</jats:italic> loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify <jats:italic>KRAS</jats:italic> , <jats:italic>BRAF</jats:italic> , and <jats:italic>NOTCH1</jats:italic> 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. </jats:p>