Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

Weiyin Zhou^{1

2}, Anja Fischer³, Martin D Ogwang⁴, Wen Luo^{1

2}, Patrick Kerchan⁵, Steven J Reynolds⁶, Constance N Tenge⁷, Pamela A Were⁸, Robert T Kuremu⁷, Walter N Wekesa⁷, Nestory Masalu⁹, Esther Kawira¹⁰, Tobias Kinyera^{4

11}, Isaac Otim^{4

11}, Ismail D Legason^{5

11}, Hadijah Nabalende^{4

11}, Leona W Ayers¹², Kishor Bhatia¹, James J Goedert¹, Mateus H Gouveia¹³, Nathan Cole^{1

2}, Belynda Hicks^{1

2}, Kristine Jones^{1

2}, Michael Hummel^{14

15}, Mathias Schlesner¹⁶, George Chagaluka¹⁷, Nora Mutalima^{18

19}, Eric Borgstein¹⁷, George N Liomba¹⁷, Steve Kamiza¹⁷, Nyengo Mkandawire¹⁷, Collins Mitambo²⁰, Elizabeth M Molyneux¹⁷, Robert Newton¹⁸, Selina Glaser³, Helene Kretzmer²¹, Michelle Manning^{1

2}, Amy Hutchinson^{1

2}, Ann W Hsing²², Yao Tettey²³, Andrew A Adjei²³, Stephen J Chanock^{1

2}, Reiner Siebert³, Meredith Yeager^{1

2}, Ludmila Prokunina-Olsson¹, Mitchell J Machiela¹, Sam M Mbulaiteye²⁴

Affiliations

¹ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
² Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
³ Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
⁴ EMBLEM Study, St. Mary's Hospital, Lacor, Gulu, Uganda.
⁵ EMBLEM Study, Kuluva Hospital, Arua, Uganda.
⁶ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ EMBLEM Study, Moi University College of Health Sciences, Eldoret, Kenya.
⁸ EMBLEM Study, Academic Model Providing Access To Healthcare (AMPATH), Eldoret, Kenya.
⁹ EMBLEM Study, Bugando Medical Center, Mwanza, Tanzania.
¹⁰ EMBLEM Study, Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹¹ EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
¹² Department of Pathology, The Ohio State University, Columbus, OH, USA.
¹³ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
¹⁴ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Berlin, Germany.
¹⁵ Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, D-10117, Berlin, Germany.
¹⁶ Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, Augsburg, Germany.
¹⁷ Departments of Pediatrics and Surgery, College of Medicine, University of Malawi, Blantyre, Malawi.
¹⁸ Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.
¹⁹ Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
²⁰ Research Department, Ministry of Health, P.O. Box 30377, Lilongwe 3, Malawi.
²¹ Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
²² Stanford Cancer Institute, Stanford University, Stanford, Palo Alto, CA, USA.
²³ Department of Pathology, University of Ghana Medical School, College of Health Sciences, P.O. Box KB 52, Korle-Bu, Accra, Ghana.
²⁴ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. mbulaits@mail.nih.gov.

PMID: 38057307
PMCID: PMC10700489
DOI: 10.1038/s41467-023-43881-0

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

Weiyin Zhou et al. Nat Commun. 2023.

. 2023 Dec 6;14(1):8081.

doi: 10.1038/s41467-023-43881-0.

Authors

Affiliations

¹ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
² Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
³ Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
⁴ EMBLEM Study, St. Mary's Hospital, Lacor, Gulu, Uganda.
⁵ EMBLEM Study, Kuluva Hospital, Arua, Uganda.
⁶ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ EMBLEM Study, Moi University College of Health Sciences, Eldoret, Kenya.
⁸ EMBLEM Study, Academic Model Providing Access To Healthcare (AMPATH), Eldoret, Kenya.
⁹ EMBLEM Study, Bugando Medical Center, Mwanza, Tanzania.
¹⁰ EMBLEM Study, Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹¹ EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
¹² Department of Pathology, The Ohio State University, Columbus, OH, USA.
¹³ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
¹⁴ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Berlin, Germany.
¹⁵ Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, D-10117, Berlin, Germany.
¹⁶ Biomedical Informatics, Data Mining and Data Analytics, University of Augsburg, Augsburg, Germany.
¹⁷ Departments of Pediatrics and Surgery, College of Medicine, University of Malawi, Blantyre, Malawi.
¹⁸ Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.
¹⁹ Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
²⁰ Research Department, Ministry of Health, P.O. Box 30377, Lilongwe 3, Malawi.
²¹ Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
²² Stanford Cancer Institute, Stanford University, Stanford, Palo Alto, CA, USA.
²³ Department of Pathology, University of Ghana Medical School, College of Health Sciences, P.O. Box KB 52, Korle-Bu, Accra, Ghana.
²⁴ Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. mbulaits@mail.nih.gov.

PMID: 38057307
PMCID: PMC10700489
DOI: 10.1038/s41467-023-43881-0

Abstract

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10^-11 and 3.74×10^-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Study participant regions and sample characteristics.**
a Map showing study countries and enrollment sites. The map was drawn using ESRI ArcGIS Pro software. No portions of this figure were imported as image components from a database; b Flow diagram of subjects and samples analyzed; c population substructure in the study population based on analysis of principal components (PC) using 787,731 genotyped uncorrelated (r2 < 0.3) SNPs outside the HLA region (triangles represent BL cases, solid circles represent controls; ‘Source data are provided as a Source Data file’).

**Fig. 2. Circos plots of detected mosaic chromosomal alterations (mCAs) and their genomic location (GRCh37).**
The outer rings are for the autosomes moving clockwise from chromosome 1 to 22. The mCAs were detected in blood cells of subjects from Kenya, Tanzania, and Uganda in the EMBLEM study. The green region is mosaic duplication events; blue region is mosaic CNLOH events; red region is mosaic copy-loss events. a mCAs detected in 701 BL cases. b mCAs detected in 3645 BL-free controls; ‘Source data are provided as a Source Data file’.

**Fig. 3. mCAs detected in paired tumor and peripheral blood leukocytes from one of the two informative BL cases.**
The figure shows three mCAs > = 2MB in size (chromosome 1q duplication, chromosome 3q deletion, and 6q deletion) detected at cell fraction (CF) ≥ 0.09 in peripheral blood leukocytes and at CF > 0.8 in tumor WGS data from the same BL patient. The mCAs were the same event types detected in similar but not identical genomic regions. a The 3 detected mCAs in WGS tumor data. b The 3 detected mCAs in SNP array data from peripheral blood leukocytes. Upper panels in the figures: Log depth of read coverage of WGS data or exponentiated Log R ratio (eLRR) of SNP data, respectively; Bottom panels in the figures: phase B allele frequency (pBAF) in WGS data or SNP array data, respectively. Gray color indicates regions with a normal state, all other colors (orange, blue, green) indicate regions with mCAs. ‘Source data are provided as a Source Data file’.

**Fig. 4. Genomic location of mCAs gains detected on chromosome 1q in 16 BL cases.**
Horizontal bar plots show regions affected by mCAs for each BL patient. Bar colors indicate median cell fraction (CF) values using a heatmap color code indicator in the bar legend. Colored boxes indicate the location of genomic regions with oncogenes from the Oncogene database and significantly mutated genes (SMGs) in BL curated from literature;^, the oncogenes or SMGs in BL (marked with an asterisk) are listed below. For each gene, vertical bar plots show the number of BL cases with mCAs overlapping the oncogene or SMG. A heatmap is included to show expression of the gene or SMG in endemic Burkitt lymphoma (eBL), sporadic Burkitt lymphoma (sBL) and germinal center B cell populations (gcBC) for relative comparisons (see online methods for details; ‘Source data are provided as a Source Data file’).

See this image and copyright information in PMC

References

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Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

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Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

Authors

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Abstract

Conflict of interest statement

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