Format

Send to

Choose Destination
Blood. 2019 Nov 7;134(19):1598-1607. doi: 10.1182/blood.2019001880.

The whole-genome landscape of Burkitt lymphoma subtypes.

Author information

1
Center for Genomic and Computational Biology and Department of Medicine, Duke University, Durham, NC.
2
Department of Pathology and Laboratory Medicine, Brown University, Providence, RI.
3
Department of Medicine, University of Massachusetts, Worcester, MA.
4
Jaramogi Oginga Odinga Teaching and Referral Hospital, Ministry of Health, Kisumu, Kenya.
5
Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
6
Bugando Medical Center, Mwanza, Tanzania.
7
Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO.
8
University of North Carolina, Chapel Hill, NC.
9
Poland Flow Cytometry Laboratory, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland.
10
Department of Pathology, University of Utah, Salt Lake City, UT.
11
Department of Pathology and Cell Biology, Columbia University, New York, NY.
12
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA.
13
Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH.
14
Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
15
The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
16
Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
17
Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany.
18
Medical Department A, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
19
Department of Pathology, Case Western Reserve University, Cleveland, OH.
20
Department of Immunology and.
21
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC.
22
Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, BC, Canada.
23
HudsonAlpha Institute for Biotechnology, Huntsville, AL; and.
24
Department of Statistical Science, Duke University, Durham, NC.

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.

PMID:
31558468
PMCID:
PMC6871305
[Available on 2020-11-07]
DOI:
10.1182/blood.2019001880
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center