Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma

Abstract

<p class="first" id="d5773488e735"> <b>Publisher's Note:</b> There is a <span class="generated">[Related article:]</span> <i>Blood</i> Commentary on this article in this issue. </p><p id="d5773488e748"> <div class="list"> <a class="named-anchor" id="d5773488e750"> <!-- named anchor --> </a> <ul class="so-custom-list"> <li id="d5773488e751"> <div class="so-custom-list-content so-ol"> <p class="first" id="d5773488e752">Tumor EBV status is more strongly associated with distinct genetic and etiological mechanisms than geographic origin. </p> </div> </li> <li id="d5773488e754"> <div class="so-custom-list-content so-ol"> <p class="first" id="d5773488e755">EBV-positive BL genomes feature fewer driver mutations despite their greater mutational load that is partly a result of increased AICDA activity. </p> </div> </li> </ul> </div> </p><p class="first" id="d5773488e759">Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as <i>SIN3A</i>, <i>USP7</i>, and <i>CHD8</i>, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients. </p><p id="d5773488e773"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/83582de2-de93-4d48-904d-556ae2aefb09/PubMedCentral/image/blood871418absf1"/> </div> <div class="panel-content"/> </div> </p>