@article{e304834e838c4d04b30ac0a9e4e084a9,
title = "Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma",
abstract = "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 SIN3A, USP7, and CHD8, 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.",
author = "Grande, {Bruno M.} and Gerhard, {Daniela S.} and Aixiang Jiang and Griner, {Nicholas B.} and Abramson, {Jeremy S.} and Alexander, {Thomas B.} and Hilary Allen and Ayers, {Leona W.} and Bethony, {Jeffrey M.} and Kishor Bhatia and Jay Bowen and Corey Casper and Choi, {John Kim} and Luka Culibrk and Davidsen, {Tanja M.} and Dyer, {Maureen A.} and Gastier-Foster, {Julie M.} and Patee Gesuwan and Greiner, {Timothy C.} and Gross, {Thomas G.} and Benjamin Hanf and Harris, {Nancy Lee} and Yiwen He and Irvin, {John D.} and Jaffe, {Elaine S.} and Jones, {Steven J.M.} and Patrick Kerchan and Nicole Knoetze and Leal, {Fabio E.} and Lichtenberg, {Tara M.} and Yussanne Ma and Martin, {Jean Paul} and Martin, {Marie Reine} and Mbulaiteye, {Sam M.} and Mullighan, {Charles G.} and Mungall, {Andrew J.} and Constance Namirembe and Karen Novik and Ariela Noy and Ogwang, {Martin D.} and Abraham Omoding and Jackson Orem and Reynolds, {Steven J.} and Rushton, {Christopher K.} and Sandlund, {John T.} and Roland Schmitz and Cynthia Taylor and Wilson, {Wyndham H.} and Wright, {George W.} and Zhao, {Eric Y.} and Marra, {Marco A.} and Morin, {Ryan D.} and Staudt, {Louis M.}",
note = "Funding Information: This work has been funded in part by the Foundation for Burkitt Lymphoma Research (http://www.foundationforburkittlymphoma.org) and in whole or in part with U.S. federal funds from the National Institutes of Health (NIH), National Cancer Institute, under contract HHSN261200800001E, and contracts HHSN261201100063C and HHSN261201100007I (Division of Cancer Epidemiology and Genetics). This work was supported by the Intramural Research Program, NIH, National Institute of Allergy and Infectious Diseases (S.J.R.); by a Terry Fox New Investigator Award (#1043); and by an operating grant from the Canadian Institutes for Health Research and a New Investigator Award from the Canadian Institutes for Health Research (R.D.M.). R.D.M. is a Michael Smith Foundation for Health Research Scholar. This work was supported by the Canadian Institutes for Health Research (FDN-143288) (M.A.M.), the American Lebanese Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital, and the NIH, National Cancer Institute (R35-CA197695-01A1 to C.G.M.). Travel funds were provided by the Canadian Institutes for Health Research (#155017), the Canadian Cancer Society (#705613), and the John Bosdet Memorial Fund (B.M.G.). Publisher Copyright: {\textcopyright} 2019 American Society of Hematology. All rights reserved.",
year = "2019",
month = mar,
day = "21",
doi = "10.1182/blood-2018-09-871418",
language = "English (US)",
volume = "133",
pages = "1313--1324",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "12",
}