Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

Mateus H Gouveia¹, Isaac Otim², Martin D Ogwang³, Mingyi Wang⁴, Bin Zhu⁴, Nathan Cole⁴, Wen Luo⁴, Belynda Hicks⁴, Kristine Jones⁴, Kathrin Oehl-Huber⁵, Leona W Ayers⁶, Stefania Pittaluga⁷, Ismail D Legason⁸, Hadijah Nabalende², Patrick Kerchan⁸, Tobias Kinyera², Esther Kawira⁹, Glen Brubaker¹⁰, Arthur G Levin⁹, Lutz Guertler¹¹, Jung Kim¹², Douglas R Stewart¹², Melissa Adde¹³, Ian Magrath¹³, Andrew W Bergen¹², Steven J Reynolds¹⁴, Meredith Yeager⁴, Kishor Bhatia¹², Adebowale A Adeyemo¹, Ludmila Prokunina-Olsson¹², Michael Dean¹², Daniel Shriner¹, Charles N Rotimi¹, Stephen Chanock¹², Reiner Siebert^#⁵, Sam M Mbulaiteye^#¹⁵

Affiliations

¹ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
² EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
³ EMBLEM Study, St. Mary's Hospital, Lacor, Gulu, Uganda.
⁴ Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁵ Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
⁶ Department of Pathology, The Ohio State University, Columbus, OH, USA.
⁷ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ EMBLEM Study, Kuluva Hospital, Arua, Uganda.
⁹ EMBLEM Study, Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹⁰ Inter-Church Medical Assistance Mission, Baltimore, MD, USA.
¹¹ Max von Pettenkofer Institute, LMU University of München, München, Germany.
¹² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
¹³ International Network for Cancer Treatment, Brussels, Belgium.
¹⁴ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. mbulaits@mail.nih.gov.

^# Contributed equally.

PMID: 33051549
PMCID: PMC8024190
DOI: 10.1038/s41375-020-01052-w

Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

Mateus H Gouveia et al. Leukemia. 2021 Apr.

. 2021 Apr;35(4):1209-1213.

doi: 10.1038/s41375-020-01052-w. Epub 2020 Oct 13.

Authors

Affiliations

¹ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
² EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
³ EMBLEM Study, St. Mary's Hospital, Lacor, Gulu, Uganda.
⁴ Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁵ Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
⁶ Department of Pathology, The Ohio State University, Columbus, OH, USA.
⁷ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ EMBLEM Study, Kuluva Hospital, Arua, Uganda.
⁹ EMBLEM Study, Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹⁰ Inter-Church Medical Assistance Mission, Baltimore, MD, USA.
¹¹ Max von Pettenkofer Institute, LMU University of München, München, Germany.
¹² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
¹³ International Network for Cancer Treatment, Brussels, Belgium.
¹⁴ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. mbulaits@mail.nih.gov.

^# Contributed equally.

PMID: 33051549
PMCID: PMC8024190
DOI: 10.1038/s41375-020-01052-w

Erratum in

Author Correction to: Endemic Burkitt lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility.
Gouveia MH, Otim I, Ogwang MD, Wang M, Zhu B, Cole N, Luo W, Hicks B, Jones K, Oehl-Huber K, Ayers LW, Pittaluga S, Legason ID, Nabalende H, Kerchan P, Kinyera T, Kawira E, Brubaker G, Levin AG, Guertler L, Kim J, Stewart DR, Adde M, Magrath I, Bergen AW, Reynolds SJ, Yeager M, Bhatia K, Adeyemo AA, Prokunina-Olsson L, Dean M, Shriner D, Rotimi CN, Chanock S, Siebert R, Mbulaiteye SM. Gouveia MH, et al. Leukemia. 2021 Apr;35(4):1224. doi: 10.1038/s41375-021-01140-5. Leukemia. 2021. PMID: 33526862 Free PMC article. No abstract available.

No abstract available

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1. Origin, ancestry, and relatedness of two second-degree relatives with endemic Burkitt lymphoma (eBL) in Northern Uganda.**
a Map of Uganda showing the capital city, Kampala (star with a circle), the boundary of the study area, and the location of the hospitals (red crosses) where the eBL cases were enrolled (see legend). Blue lines in the map mark all-season rivers in Uganda as a surrogate of near-homogenous high precipitation that favors high malaria transmission throughout the country. The zoom-in shows seven subregions (#1–7) in the study area and heterogeneity in prevalence of *Plasmodium falciparum* malaria measured in children aged 0–15 years during the study period (details in Supplementary data [ref. 47]). Pie charts show genomic ancestry and identity by descent (IBD) estimates. The ancestry analysis used the same methodology and African reference populations (details in Gouveia et al. [2]). b Pathology and immunohistochemistry (IHC) of eBL tumors. Staining patterns of tumors for Case 1 and Case 2 were similar. The top two rows show: Hematoxylin and Eosin (H&E) atypical lymphocytes, CD20 positive (Dako, Carpinteria, CA, USA), CD10 positive (Novocastra, Bannockburn, IL, USA), Ki67 positive (Dako, Carpinteria, CA, USA), EBER positive (in situ hybridization [ISH]) EBV (Ventana, Tuscon, AZ, USA); The bottom two rows show: CD3 negative in atypical cells (Dako, Carpinteria, CA, USA), BCL-6 positive (Dako, Carpinteria, CA, USA) BCL-2 negative (Dako, Carpinteria, CA, USA), MYC protein positive (Epitomics, Burlingame, CA, USA); MYC translocation positive (only Case 1), fluorescent in situ hybridization probe (FISH) (Vysis LSI MYC Dual Color Break Apart Rearrangement Probe, Abbott Molecular Inc., Des Plaines, IL, USA). Images are ×20 magnification. Scale bar 25 μm. c Genome-wide detection of chromosomal imbalances in FFPE tumor tissue by OncoScan Array analysis. For each tumor the imbalance and B-allele frequency plots are shown. The upper panel depicts case 1 (male) in which a loss at the IGK-locus in 2p11 (left arrow), a copy-number neutral loss of 17p13.3p13.1 (including the gene *TP53*, middle arrow) and a heterozygous loss in 18q21.32 (including the gene *CCBE1*, right arrow) were called. The lower panel shows the results of case 2 with loss at the IGH-locus in 14q32 (arrow) and a probable (subclonal) gain in 1q which was just below the diagnostic threshold for calling by the evaluation pipeline.

See this image and copyright information in PMC

References

1. Leoncini L, Campo E, Stein H, Harris NL, Jaffe ES, Kluin PM. Burkitt-like lymphoma with 11q aberration. In: WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed France, Lyon: IARC; 2017. p. 334.
1. Gouveia MH, Bergen AW, Borda V, Nunes K, Leal TP, Ogwang MD, et al. Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the ‘endemic Burkitt Lymphoma belt’. PLoS Genet. 2019;15:e1008027. doi: 10.1371/journal.pgen.1008027. - DOI - PMC - PubMed
1. Legason ID, Pfeiffer RM, Udquim K-I, Bergen AW, Gouveia MH, Kirimunda S, et al. Evaluating the causal link between malaria infection and endemic burkitt lymphoma in Northern Uganda: a mendelian randomization study. EBioMedicine. 2017;25:58–65. doi: 10.1016/j.ebiom.2017.09.037. - DOI - PMC - PubMed
1. Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB, et al. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019;133:1313–24. doi: 10.1182/blood-2018-09-871418. - DOI - PMC - PubMed
1. López C, Kleinheinz K, Aukema SM, Rohde M, Bernhart SH, Hübschmann D, et al. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma. Nat Commun. 2019;10:1459. doi: 10.1038/s41467-019-08578-3. - DOI - PMC - PubMed

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Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

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Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

Authors

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Erratum in

Conflict of interest statement

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