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Blood. 2019 Jan 7. pii: blood-2018-09-871418. doi: 10.1182/blood-2018-09-871418. [Epub ahead of print]

Genome-wide discovery of somatic coding and non-coding 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, NIH, Bethesda, MD, United States.
3
Center for Lymphoma, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.
5
Nationwide Children's Hospital, Columbus, OH, United States.
6
Department of Pathology, The Ohio State University, Columbus, OH, United States.
7
George Washington University, Washington, DC, United States.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, United States.
9
Infectious Disease Research Institute, Seattle, WA, United States.
10
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States.
11
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
12
Cancer Informatics Branch, National Cancer Institute, NIH, Bethesda, MD, United States.
13
Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, United States.
14
Departments of Pathology and Pediatrics, The Ohio State University, Columbus, OH, United States.
15
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States.
16
Center for Global Health, National Cancer Institute, NIH, Rockville, MD, United States.
17
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
18
Foundation for Burkitt Lymphoma Research, Geneva, Switzerland.
19
Laboratory of Pathology, Clinical Center, National Cancer Institute, NIH, Bethesda, MD, United States.
20
EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
21
Instituto Nacional de Cancer, Brazil.
22
Uganda Cancer Institute, Kampala, Uganda.
23
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
24
EMBLEM Study, St. Mary's Hospital Lacor, Gulu, Uganda.
25
Hem-Onc, Uganda Cancer Institute, Kampala, Uganda.
26
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States.
27
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States.
28
Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Rockville, MD, United States.
29
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; rdmorin@sfu.ca.

Abstract

Though 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 over 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 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 BL patients 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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