The whole-genome landscape of Burkitt lymphoma subtypes

生物 遗传学 基因 癌症研究 基因组 病毒学
作者
Razvan Panea,Cassandra Love,Jennifer R. Shingleton,Anupama Reddy,Jeffrey A. Bailey,Ann M. Moormann,Juliana A. Otieno,John Michael Ong’echa,Cliff I. Oduor,Kristin Schroeder,Nestory Masalu,Nelson J. Chao,Megan J. Agajanian,Michael B. Major,Yuri Fedoriw,Kristy L. Richards,Grzegorz Rymkiewicz,Rodney R. Miles,Bachir Alobeid,Govind Bhagat,Christopher R. Flowers,Sarah L. Ondrejka,Eric D. Hsi,William W.L. Choi,Rex Au-Yeung,Wolfgang Hartmann,Georg Lenz,Howard Meyerson,Yen‐Yu Lin,Yuan Zhuang,Micah A. Luftig,Alexander Waldrop,Tushar Dave,Devang Thakkar,Harshit Sahay,Guojie Li,Brooke C. Palus,Vidya Seshadri,So Young Kim,Randy D. Gascoyne,Shawn Levy,Minerva Mukhopadyay,David B. Dunson,Sandeep S. Davé
出处
期刊:Blood [American Society of Hematology]
卷期号:134 (19): 1598-1607 被引量:141
标识
DOI:10.1182/blood.2019001880
摘要

Abstract Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry–based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
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