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Blood. 2019 Mar 21;133(12):1313-1324. doi: 10.1182/blood-2018-09-871418. Epub 2019 Jan 7.

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

Author information

1
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
2
Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
3
Center for Lymphoma, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN.
5
Nationwide Children's Hospital, Columbus, OH.
6
Department of Pathology, The Ohio State University, Columbus, OH.
7
George Washington University, Washington, DC.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.
9
Infectious Disease Research Institute, Seattle, WA.
10
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
11
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
12
Cancer Informatics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
13
Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD.
14
Departments of Pathology and Pediatrics, The Ohio State University, Columbus, OH.
15
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
16
Center for Global Health, National Cancer Institute, National Institutes of Health, Rockville, MD.
17
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
18
Foundation for Burkitt Lymphoma Research, Geneva, Switzerland.
19
Laboratory of Pathology, Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD.
20
EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
21
Programa de Oncovirologia, Instituto Nacional de Câncer José de Alencar, Rio de Janeiro, Brazil.
22
Uganda Cancer Institute, Kampala, Uganda.
23
Memorial Sloan Kettering Cancer Center, New York, NY.
24
Weill Cornell Medical College, New York, NY.
25
EMBLEM Study, St. Mary's Hospital Lacor, Gulu, Uganda.
26
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.
27
Lymphoid Malignancies Branch, Center for Cancer Research and.
28
Biometric Research Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Rockville, MD.

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.

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