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Background: Human herpesvirus 8 (HHV8), the infectious cause of Kaposi sarcoma, varies dramatically across Africa, suggesting that cofactors correlated with large-area geographic or environmental characteristics may influence risk of infection. Variation in HHV8 seropositivity across small-area regions within countries in Africa is unknown. We investigated this issue in Uganda, where Kaposi sarcoma distribution is uneven and well described.Methods: Archival samples from individuals aged 15-59 years randomly selected from a nationally representative 2004-2005 human immunodeficiency virus-AIDS serobehavioral survey were tested for HHV8 seropositivity with use of enzyme immunoassays based on synthetic peptides from the K8.1 and orf65 viral genes. Adjusted odds ratios and 95% confidence intervals (CIs) of association of HHV8 seropositivity with demographic risk factors were estimated.Results: Among 2681 individuals tested, HHV8 seropositivity was 55.4%. HHV8 seropositivity was lower in female than in male persons (adjusted odds ratio, 0.82 [95% CI, 0.69-0.97]) and increased 2.2% (95% CI, 1.0%-3.6%) in female persons and 1.2% (95% CI, 1.0%-2.3%) in male persons per year of age. HHV8 seropositivity was inversely associated with education ( P = .01, for trend) and was elevated in the West Nile region, compared with the Central region (adjusted odds ratio, 1.49 [95% CI, 1.02-2.18]) but not with other regions.Conclusions: Our findings suggest that HHV8 seropositivity in Uganda may be influenced by cofactors correlated with small-area geography, age, sex, and education. [ABSTRACT FROM AUTHOR]

Background: Although human herpesvirus 8 (HHV-8), the etiologic agent for Kaposi's sarcoma, can be detected in peripheral blood, blood-borne transmission of this virus has not been demonstrated. We studied the association between HHV-8 seropositivity and transfusion history among children with sickle-cell disease in Uganda, where HHV-8 infection is common in blood donors.Methods: We studied 600 children (aged 0-16 years) with sickle-cell disease at Mulago Hospital, Kampala, from November 2001 through April 2002. By design, about half had previously been transfused. HHV-8 serostatus was determined using enzyme-linked immunosorbent assays for antibodies against HHV-8 proteins K8.1 and orf 73. We used logistic regression to test for an association between HHV-8 serostatus and transfusion history and a Markov model to estimate the transmission risk per transfusion and the cumulative risk from community (i.e., nontransfusion) sources. Statistical tests were two-sided.Results: HHV-8 antibodies were detected in 117 of 561 (21%) children with unambiguous K8.1 results. HHV-8 seroprevalence among the never-transfused children increased with age from 7% in children aged 0-2 years to 32% in those aged 13-16 years (P(trend)<.001). HHV-8 seropositivity was more frequent in transfused than never-transfused children (24% versus 17%, odds ratio = 1.48, 95% confidence interval [CI] = 0.97 to 2.26; P =.07). Seropositivity increased with number of reported transfusions, with age-adjusted odds ratios of 0.97 (95% CI = 0.54 to 1.75), 1.13 (95% CI = 0.59 to 2.17), 1.76 (95% CI = 0.81 to 3.83), and 2.17 (95% CI = 1.18 to 3.99) for children with one, two, three, or four or more transfusions, respectively (P(trend) =.007). Overall, the estimated HHV-8 transmission risk was 2.6% per transfusion (95% CI = 1.9% to 3.3%), whereas the annual risk of infection unrelated to transfusion was 2.7% (95% CI = 1.7% to 3.7%).Conclusion: Our study suggests that blood transfusion is associated with a small risk of HHV-8 transmission. In Uganda, this risk is approximately equivalent to the 1-year cumulative risk of infection from community sources. [ABSTRACT FROM AUTHOR]

The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. We characterized a variable number tandem repeat within TERT intron 6 (VNTR6-1, 38-bp repeat unit) and observed a strong association between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals within TERT intron 4. Specifically, VNTR6-1 fully explained the GWAS signals for rs2242652 and partially for rs10069690. VNTR6-1, rs10069690 and their haplotypes were associated with multi-cancer risk and age-related telomere shortening. Both variants reduce TERT expression through alternative splicing and nonsense-mediated decay: rs10069690-T increases intron 4 retention and VNTR6-1-Long expands a polymorphic G quadruplex (G4, 35-113 copies) within intron 6. Treatment with G4-stabilizing ligands decreased the fraction of the functional telomerase-encoding TERT full-length isoform, whereas CRISPR/Cas9 deletion of VNTR6-1 increased this fraction and apoptosis while reducing cell proliferation. Thus, VNTR6-1 and rs10069690 regulate the expression and splicing of TERT transcripts encoding both functional and nonfunctional telomerase. Altered TERT isoform ratios might modulate cellular longevity and replicative potential at homeostasis and in response to environmental factors, thus selectively contributing to the reduced or elevated cancer risk conferred by this locus., Competing Interests: Competing interests None declared.

Introduction: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown., Materials and Methods: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6-11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction., Results: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0&#95;38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10 - 4 ). Two metabolites (triacylglyceride (18:0&#95;38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00)., Conclusion: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: In sub-Saharan Africa (SSA), Plasmodium falciparum causes most of the malaria cases. Despite its crucial roles in disease severity and drug resistance, comprehensive data on Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) are sparse in SSA. This study summarizes available information on genetic diversity and MOI, focusing on key markers (msp-1, msp-2, glurp, and microsatellites). The systematic review aimed to evaluate their influence on malaria transmission dynamics and offer insights for enhancing malaria control measures in SSA., Methods: The review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Two reviewers conducted article screening, assessed the risk of bias (RoB), and performed data abstraction. Meta-analysis was performed using the random-effects model in STATA version 17., Results: The review included 52 articles: 39 cross-sectional studies and 13 Randomized Controlled Trial (RCT)/cohort studies, involving 11,640 genotyped parasite isolates from 23 SSA countries. The overall pooled mean expected heterozygosity was 0.65 (95% CI: 0.51-0.78). Regionally, values varied: East (0.58), Central (0.84), Southern (0.74), and West Africa (0.69). Overall pooled allele frequencies of msp-1 alleles K1, MAD20, and RO33 were 61%, 44%, and 40%, respectively, while msp-2 I/C 3D7 and FC27 alleles were 61% and 55%. Central Africa reported higher frequencies (K1: 74%, MAD20: 51%, RO33: 48%) than East Africa (K1: 46%, MAD20: 42%, RO33: 31%). For msp-2, East Africa had 60% and 55% for I/C 3D7 and FC27 alleles, while West Africa had 62% and 50%, respectively. The pooled allele frequency for glurp was 66%. The overall pooled mean MOI was 2.09 (95% CI: 1.88-2.30), with regional variations: East (2.05), Central (2.37), Southern (2.16), and West Africa (1.96). The overall prevalence of polyclonal Plasmodium falciparum infections was 63% (95% CI: 56-70), with regional prevalences as follows: East (62%), West (61%), Central (65%), and South Africa (71%)., Conclusion: The study shows substantial regional variation in Plasmodium falciparum parasite genetic diversity and MOI in SSA. These findings suggest a need for malaria control strategies and surveillance efforts considering regional-specific factors underlying Plasmodium falciparum infection., (© 2024. The Author(s).)

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10 -6 ), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10 -8 ), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10 -6 ). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that occurs worldwide. A study of BL in the US National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program during 1973 to 2005 (n = 3043) revealed three age-specific incidence peaks of BL and rates that were rising. We studied BL cases diagnosed in SEER 22 during 2000 to 2019 (n = 11 626) to investigate age-specific BL incidence rates and temporal trends. The age-standardized BL incidence rate was 3.96/million person-years, with a 2.85:1 male-to-female ratio. The BL rate among both Hispanic and White individuals was higher than in Black individuals (4.52, 4.12 vs 3.14). Age-specific BL rates showed peaks during pediatric, adult and elderly years in males and pediatric and elderly peaks in females. Based on 4524 BL cases with HIV status (SEER 13), only one peak in adult males (45 years) was observed. Overall age-standardized BL incidence rates rose 1.2%/year (not significant) up to 2009 then fell significantly by 2.4%/year thereafter. Temporal trends in BL rates during 2000 to 2019 varied with age group as pediatric BL rates rose 1.1%/year, while elderly BL rates fell 1.7%/year and adult BL rates rose 3.4%/year until 2007 before falling 3.1%/year thereafter. Overall survival from BL was 64% at 2 years, being highest in pediatric patients and lowest in Black and elderly individuals vs other subgroups. Survival improved by 20% between 2000 and 2019. Our data suggest that BL age-specific incidence rates are multimodal and that overall BL rates rose up to 2009 and then fell, suggesting changes in etiological factors or diagnosis., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele ( IFNL4 -dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4 -dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4 -dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Background: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL)., Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models., Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types., Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis., Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer., (©2023 American Association for Cancer Research.)

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Burkitt lymphoma (BL) has a cure rate of around 95% when treated with chemo-immunotherapy that is standard of care in high-income countries (Minard-Colin et al., 2020, New England Journal of Medicine 382, 2207-2219), but currently, more than 50% of children and young adults with endemic BL (Epstein Barr virus driven BL) in sub-Saharan Africa (SSA) do not survive. Treatment for BL is largely free of charge, but there is limited access to reliable diagnostic services leading to significant delays and misdiagnoses. Innovations in histopathology such as whole slide imaging and the use of novel diagnostic approaches, in particular using circulating cell-free viral and/or lymphoma DNA (liquid biopsy), could increase access to timely and reliable diagnosis and improve outcomes in SSA., Competing Interests: The authors declare that they have no relevant conflict of interest., (© The Author(s) 2023.)

Endemic Burkitt lymphoma (eBL) is a pediatric cancer coendemic with malaria in sub-Saharan Africa, suggesting an etiological link between them. However, previous cross-sectional studies of limited geographic areas have not found a convincing association. We used spatially detailed data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study to assess this relationship. EMBLEM is a case-control study of eBL from 2010 through 2016 in six regions of Kenya, Uganda, and Tanzania. To measure the intensity of exposure to the malaria parasite, Plasmodium falciparum , among children in these regions, we used high-resolution spatial data from the Malaria Atlas Project to estimate the annual number of P. falciparum infections from 2000 through 2016 for each of 49 districts within the study region. Cumulative P. falciparum exposure, calculated as the sum of annual infections by birth cohort, varied widely, with a median of 47 estimated infections per child by age 10, ranging from 4 to 315 infections. eBL incidence increased 39% for each 100 additional lifetime P. falciparum infections (95% CI: 6.10 to 81.04%) with the risk peaking among children aged 5 to 11 and declining thereafter. Alternative models using estimated annual P. falciparum infections 0 to 10 y before eBL onset were inconclusive, suggesting that eBL risk is a function of cumulative rather than recent cross-sectional exposure. Our findings provide population-level evidence that eBL is a phenotype related to heavy lifetime exposure to P. falciparum malaria and support emphasizing the link between malaria and eBL.

Burkitt lymphoma (BL) is an aggressive form of B cell lymphoma that can affect children and adults. The study of BL led to the identification of the first recurrent chromosomal aberration in lymphoma, t(8;14)(q24;q32), and subsequent discovery of the central role of MYC and Epstein-Barr virus (EBV) in tumorigenesis. Most patients with BL are cured with chemotherapy but those with relapsed or refractory disease usually die of lymphoma. Historically, endemic BL, non-endemic sporadic BL and the immunodeficiency-associated BL have been recognized, but differentiation of these epidemiological variants is confounded by the frequency of EBV positivity. Subtyping into EBV + and EBV - BL might better describe the biological heterogeneity of the disease. Phenotypically resembling germinal centre B cells, all types of BL are characterized by dysregulation of MYC due to enhancer activation via juxtaposition with one of the three immunoglobulin loci. Additional molecular changes commonly affect B cell receptor and sphingosine-1-phosphate signalling, proliferation, survival and SWI-SNF chromatin remodelling. BL is diagnosed on the basis of morphology and high expression of MYC. BL can be effectively treated in children and adolescents with short durations of high dose-intensity multiagent chemotherapy regimens. Adults are more susceptible to toxic effects but are effectively treated with chemotherapy, including modified versions of paediatric regimens. The outcomes in patients with BL are good in high-income countries with low mortality and few late effects, but in low-income and middle-income countries, BL is diagnosed late and is usually treated with less-effective regimens affecting the overall good outcomes in patients with this lymphoma., (© 2022. Springer Nature Limited.)

Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered., (© 2022. The Author(s).)

Epstein-Barr virus (EBV) is associated with endemic Burkitt lymphoma (eBL), but the contribution of EBV variants is ill-defined. Studies of EBV whole genome sequences (WGS) have identified phylogroups that appear to be distinct for Asian versus non-Asian EBV, but samples from BL or Africa, where EBV was first discovered, are under-represented. We conducted a phylogenetic analysis of EBV WGS and LMP-1 sequences obtained primarily from BL patients in Africa and representative non-African EBV from other conditions or regions using data from GenBank, Sequence Read Archive, or Genomic Data Commons for the Burkitt Lymphoma Genome Sequencing Project (BLGSP) to generate data to support the use of a simpler biomarker of geographic or phenotypic associations. We also investigated LMP-1 patterns in 414 eBL cases and 414 geographically matched controls in the Epidemiology of Burkitt Lymphoma in East African children and minors (EMBLEM) study using LMP-1 PCR and Sanger sequencing. Phylogenetic analysis revealed distinct genetic patterns of African versus Asian EBV sequences. We identified 281 single nucleotide variations (SNVs) in LMP-1 promoter and coding region, which formed 12 unique patterns (A to L). Nine patterns (A, AB, C, D, F, I, J, K and L) predominated in African EBV, of which four were found in 92% of BL samples (A, AB, D, and H). Predominant patterns were B and G in Asia and H in Europe. EBV positivity in peripheral blood was detected in 95.6% of EMBLEM eBL cases versus 79.2% of the healthy controls (odds ratio [OR] =3.83; 95% confidence interval 2.06-7.14). LMP-1 was successfully sequenced in 66.7% of the EBV DNA positive cases but in 29.6% of the controls (ORs ranging 5-11 for different patterns). Four LMP-1 patterns (A, AB, D, and K) were detected in 63.1% of the cases versus 27.1% controls (ORs ranges: 5.58-11.4). Dual strain EBV infections were identified in WGS and PCR-Sanger data. In conclusion, EBV from Africa is phylogenetically separate from EBV in Asia. Genetic diversity in LMP-1 formed 12 patterns, which showed promising geographic and phenotypic associations. Presence of multiple strain infection should be considered in efforts to refine or improve EBV markers of ancestry or phenotype., Lay Summary: Epstein-Barr virus (EBV) infection, a ubiquitous infection, contributes to the etiology of both Burkitt Lymphoma (BL) and nasopharyngeal carcinoma, yet their global distributions vary geographically with no overlap. Genomic variation in EBV is suspected to play a role in the geographical patterns of these EBV-associated cancers, but relatively few EBV samples from BL have been comprehensively studied. We sought to compare phylogenetic patterns of EBV genomes obtained from BL samples in Africa and from tumor and non-tumor samples from elsewhere. We concluded that EBV obtained from BL in Africa is genetically separate from EBV in Asia. Through comprehensive analysis of nucleotide variations in EBV's LMP-1 gene, we describe 12 LMP-1 patterns, two of which (B and G) were found mostly in Asia. Four LMP-1 patterns (A, AB, D, and F) accounted for 92% of EBVs sequenced from BL in Africa. Our results identified extensive diversity of EBV, but BL in Africa was associated with a limited number of variants identified, which were different from those identified in Asia. Further research is needed to optimize the use of PCR and sequencing to study LMP-1 diversity for classification of EBV variants and for use in epidemiologic studies to characterize geographic and/or phenotypic associations of EBV variants with EBV-associated malignancies, including eBL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liao, Liu, Chin, Li, Hung, Tsai, Otim, Legason, Ogwang, Reynolds, Kerchan, Tenge, Were, Kuremu, Wekesa, Masalu, Kawira, Ayers, Pfeiffer, Bhatia, Goedert, Lo and Mbulaiteye.)

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in regions of equatorial Africa where P. falciparum malaria is holoendemic. The tumor is consistently associated with Epstein-Barr virus (EBV). Screening for EBV DNA in plasma in a high-risk population in Hong Kong has been shown to be useful in facilitating the early diagnosis of nasopharyngeal carcinoma, another EBV-associated tumor. Here, we investigate plasma EBV as a diagnostic marker for eBL in children in Uganda. We studied plasma specimens from 25 children with eBL and 25 controls matched for age (<3-16 years), gender and geography, including many with asymptomatic P. falciparum infection. These specimens were previously collected under the auspices of the EMBLEM (Epidemiology of Burkitt lymphoma in East African children and minors) study. After cell-free DNA isolation, plasma EBV DNA was measured using a quantitative PCR assay that amplifies the large internal repeats of the EBV genome. All children with eBL had measurable plasma EBV, as compared to 84% of control children. The median plasma EBV DNA level was 5.23 log 10 copies/mL (interquartile range 3.54-6.08 log 10 copies/mL) in children with eBL. In contrast, the median plasma EBV DNA level was 0.37 log 10 copies/mL (interquartile range 0.18-1.05 log 10 copies/mL) in children without lymphoma. An EBV threshold of 2.52 log 10 copies/mL yielded a sensitivity of.88 and a specificity of 1. The estimated AUC was 0.936 (95% CI: 0.8496 - 1.00) for the corresponding ROC curve. Plasma EBV copy number did not depend on age, gender, or malaria screening status. However, two control children with asymptomatic P. falciparum infection and parasitemia also had high plasma EBV copy number. Our analysis suggests that measurements of EBV copy number in plasma may be useful in identifying children with eBL versus control children. A promising area for future research is the differentiation of high copy number associated with tumor versus high copy number associated with asymptomatic parasitemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xian, Kinyera, Otim, Sampson, Nabalende, Legason, Stone, Ogwang, Reynolds, Kerchan, Bhatia, Goedert, Mbulaiteye and Ambinder.)

Competing Interests: I declare no competing interests.

Background: Falciparum and endemic Burkitt lymphoma (eBL) are co-endemic in Africa, but the malaria experience in eBL patients is unknown. A lower prevalence of falciparum has been reported in eBL patients, but those results are anecdotally attributed to pre-enrollment anti-malaria treatment., Methods: We studied 677 eBL patients and 2920 community controls aged 0-15 years enrolled in six regions in Uganda, Tanzania, and Kenya during 2010-2016. Falciparum was diagnosed using thick blood film microscopy (TFM) and antigen-capture rapid diagnostic tests (RDTs). Guardians of the children answered a 40-item structured questionnaire about their child's pre-enrollment lifetime malaria history and treatment, demographics, socioeconomics, animal exposures, fevers, and hospitalizations. We utilized exploratory factor analysis to reduce the 40 questionnaire variables into six factors, including Inpatient malaria and Outpatient malaria factors that were surrogates of pre-enrollment anti-malaria treatment. The six factors accounted for 83-90% of the variance in the questionnaire data. We calculated odds ratios and 95% confidence intervals (OR 95% CI) of association of eBL with falciparum positivity, defined as positive both on TFM or RDTs, or only RDTs (indicative of recent infection) or TFM (indicative of current falciparum infection) versus no infection, using multivariable logistic regression, controlling for group of age (0-2, 3-5, 6-8, 9-11 and 12-15 years), sex, and study site and the afore-mentioned pre-enrollment factors., Results: The prevalence of falciparum infection was 25.6% in the eBL cases and 45.7% in community controls (aOR = 0.43, 95% CI: 0.40, 0.47; P < 0.0001). The results were similar for recent falciparum infection (6.9% versus 13.5%, aOR = 0.44, 95% CI: 0.38, 0.50; P < 0.0001) and current falciparum infection (18.7% versus 32.1%, aOR = 0.47, 95% CI: 0.43, 0.51; P < 0.0001). These aORs for any, recent and current falciparum infection did not change when we adjusted for pre-enrollment factors (aORs = 0.46, =0.44, and = 0.51, respectively) were significantly lower in stratified analysis for any infection in children < 5 years (aOR = 0.46; 95% CI: 0.29, 0.75) or ≥ 10 years (aOR = 0.47; 95% CI: 0.32, 0.71)., Conclusion: Our study results reduce support for pre-enrollment antimalaria treatment as a sole explanation for the observed lower falciparum prevalence in eBL cases and open a space to consider alternative immunology-based hypotheses.

Background/objectives: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil., Subjects/methods: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas)., Results: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m 2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects., Conclusions: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13-2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02-1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r 2  = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.

Background: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa and is linked to Plasmodium falciparum ( Pf ) malaria infection, one of the most common and deadly childhood infections in Africa; however, the role of Pf genetic diversity is unclear. A potential role of Pf genetic diversity in eBL has been suggested by a correlation of age-specific patterns of eBL with the complexity of Pf infection in Ghana, Uganda, and Tanzania, as well as a finding of significantly higher Pf genetic diversity, based on a sensitive molecular barcode assay, in eBL cases than matched controls in Malawi. We examined this hypothesis by measuring diversity in Pf- serine repeat antigen-5 ( Pfsera5 ), an antigenic target of blood-stage immunity to malaria, among 200 eBL cases and 140 controls, all Pf polymerase chain reaction (PCR)-positive, in Malawi., Methods: We performed Pfsera5 PCR and sequencing (~3.3 kb over exons II-IV) to determine single or mixed Pf SERA5 infection status. The patterns of Pfsera5 PCR positivity, mixed infection, sequence variants, and haplotypes among eBL cases, controls, and combined/pooled were analyzed using frequency tables. The association of mixed Pfsera5 infection with eBL was evaluated using logistic regression, controlling for age, sex, and previously measured Pf genetic diversity., Results: Pfsera5 PCR was positive in 108 eBL cases and 70 controls. Mixed Pf SERA5 infection was detected in 41.7% of eBL cases versus 24.3% of controls; the odds ratio (OR) was 2.18, and the 95% confidence interval (CI) was 1.12-4.26, which remained significant in adjusted results (adjusted odds ratio [aOR] of 2.40, 95% CI of 1.11-5.17). A total of 29 nucleotide variations and 96 haplotypes were identified, but these were unrelated to eBL., Conclusions: Our results increase the evidence supporting the hypothesis that infection with mixed Pf infection is increased with eBL and suggest that measuring Pf genetic diversity may provide new insights into the role of Pf infection in eBL.

Platelet counts are decreased in Plasmodium falciparum malaria, which is aetiologically linked with endemic Burkitt lymphoma (eBL). However, the pattern of platelet counts in eBL cases is unknown. We studied platelet counts in 582 eBL cases and 2 248 controls enrolled in a case-control study in Uganda, Tanzania and Kenya (2010-2016). Mean platelet counts in controls or eBL cases with or without malaria-infection in controls versus eBLcases were compared using Student's t-test. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using multiple logistic regression, controlling for age, sex, haemoglobin and white blood cell counts. Platelets were decreased with malaria infection in the controls [263 vs. 339 × 10 9 platelets/l, P < 0·0001; adjusted OR (aOR) = 3·42, 95% CI: 2·79-4·18] and eBL cases (314 vs. 367 × 10 9 platelets/l, P-value = 0·002; aOR = 2·36, 95% CI: 1·49-3·73). Unexpectedly, platelets were elevated in eBL cases versus  controls in overall analyses (mean: 353 vs. 307 × 10 9 platelets/l, P < 0·0001; aOR = 1·41; 95% CI: 1·12-1·77), and when restricted to malaria-positive (mean 314 vs. 263 × 10 9 platelets/l, P < 0·0001; OR = 2·26; 95% CI: 1·56-3·27) or malaria-negative (mean 367 vs. 339 × 10 9 platelets/l, P < 0·001; OR = 1·46; 95% CI: 1·17-1·83) subjects. Platelets were decreased with malaria infection in controls and eBL cases but elevated with eBL., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Endemic Burkitt lymphoma (eBL) is an aggressive B cell non-Hodgkin lymphoma associated with antigenic stimulation from Plasmodium falciparum malaria. Whether eBL risk is related to malaria parasite density is unknown. To address this issue, children with eBL, asymptomatic and clinical malaria, as a surrogate of malaria parasite density, were assessed., Methods: Malaria-related laboratory results (parasite density, haemoglobin, platelet count, and white cell count [WBC]) count) were compiled for 4019 eBL cases and 80,532 subjects evaluated for asymptomatic malaria or clinical malaria (severe malaria anaemia, hyperparasitaemia, cerebral malaria, malaria prostration, moderate malaria, and mild malaria) in 21 representative studies published in Africa (mostly East Africa) and 850 eBL cases and 2878 controls with primary data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) case-control study in Uganda, Tanzania, and Kenya. The average values of malaria-related laboratory results were computed by condition and trends across single-year age groups were assessed using regression and spline models., Results: Overall, malaria infection or malaria was diagnosed in 37,089 of children compiled from the literature. Children with eBL and asymptomatic parasitaemia/antigenaemia, but not those with clinical malaria, were closest in their mean age (age 7.1-7.2 vs. 7.4-9.8 years), haemoglobin level (10.0-10.4 vs. 11.7-12.3 g/dL), malaria parasite density (2800 vs. 1827-7780 parasites/µL), platelet count (347,000-353,000 vs. 244,000-306,000 platelets/µL), and WBC count (8180-8890 vs. 7100-7410 cells/µL). Parasite density in these two groups peaked between four to five years, then decreased steadily thereafter; conversely, haemoglobin showed a corresponding increase with age. Children with clinical malaria were markedly different: all had an average age below 5 years, had dramatically elevated parasite density (13,905-869,000 parasites/µL) and dramatically decreased platelet count (< 159,000 platelets/µL) and haemoglobin (< 7 g/dL)., Conclusions: eBL and asymptomatic parasitaemia/antigenaemia, but not clinical malaria, were the most similar conditions with respect to mean age and malaria-related laboratory results. These results suggest that children with asymptomatic parasitaemia/antigenaemia may be the population at risk of eBL.

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0-15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%) or differed by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR = 0·59, 95% CI 0·38-0·91), HLA-B*41 (aOR = 0·36, 95% CI 0·13-1·00), and HLA-B*58 alleles (aOR = 0·59, 95% CI 0·36-0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR = 0·57, 95% CI 0·40-0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR = 2·19, 95% CI 1·42-3·37). Our results suggest that variation in HLA may be associated with eBL risk., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in sub-Saharan African countries, however, few epidemiologic studies have been undertaken and none attempted enrolling cases from multiple countries. We therefore conducted a population-based case-control study of eBL in children aged 0-15 years old in six regions in Northern Uganda, Northern Tanzania and Western Kenya, enrolling 862 suspected cases and 2,934 population controls (response rates 98.5-100%), and processing ~40,000 vials of samples using standardized protocols. Risk factor questionnaires were administered, and malaria period prevalence was measured using rapid diagnostic tests (RDTs). A total of 80.9% of the recruited cases were diagnosed as eBL; 61.4% confirmed by histology. Associations with eBL risk were computed using logistic regression models adjusted for relevant confounders. Associations common in at least two countries were emphasized. eBL risk was decreased with higher maternal income and paternal education and elevated with history of inpatient malaria treatment >12 months before enrollment. Reporting malaria-attributed fever up to 6 months before enrollment and malaria-RDT positivity at enrollment were associated with decreased eBL risk. Conversely, reporting exposure to mass malaria suppression programs (e.g., indoor residual insecticide) was associated with elevated risk. HIV seropositivity was associated with elevated eBL risk, but the relative impact was small. The study shows that it is feasible to conduct networked, multisite population-based studies of eBL in Africa. eBL was inversely associated with socioeconomic status, positively associated with inpatient malaria treatment 12 months ago and with living in areas targeted for malaria suppression, which support a role of malaria in eBL., (© 2019 UICC.)

Background: The discovery of Epstein-Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma-endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor., Methods: We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired t tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year., Results: Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls ( P ≤ 0.0003). Burkitt lymphoma-associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations., Conclusions: Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children., Impact: The Burkitt lymphoma-specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research., (©2019 American Association for Cancer Research.)

Age-related cognitive decline (ACD) is the gradual process of decreasing of cognitive function over age. Most genetic risk factors for ACD have been identified in European populations and there are no reports in admixed Latin American individuals. We performed admixture mapping, genome-wide association analysis (GWAS), and fine-mapping to examine genetic factors associated with 15-year cognitive trajectory in 1,407 Brazilian older adults, comprising 14,956 Mini-Mental State Examination measures. Participants were enrolled as part of the Bambuí-Epigen Cohort Study of Aging. Our admixture mapping analysis identified a genomic region (3p24.2) in which increased Native American ancestry was significantly associated with faster ACD. Fine-mapping of this region identified a single nucleotide polymorphism (SNP) rs142380904 (β = -0.044, SE = 0.01, p = 7.5 × 10 -5 ) associated with ACD. In addition, our GWAS identified 24 associated SNPs, most in genes previously reported to influence cognitive function. The top six associated SNPs accounted for 18.5% of the ACD variance in our data. Furthermore, our longitudinal study replicated previous GWAS hits for cognitive decline and Alzheimer's disease. Our 15-year longitudinal study identified both ancestry-specific and cosmopolitan genetic variants associated with ACD in Brazilians, highlighting the need for more trans-ancestry genomic studies, especially in underrepresented ethnic groups.

The discovery of Epstein-Barr virus (EBV) in 1964 gave birth to the field of viral oncology. Despite significant scientific and clinical developments in research on several other viruses discovered and linked to cancer risk much later, our understanding of EBV as a carcinogen and a possible target for therapeutic interventions remains limited. In this issue of Cancer Research , Chakravorty and colleagues present results of massive reanalysis of public RNA-sequencing data for 291 control and 1,051 tumor samples representing 15 cancer types. Their paired analysis of the viral and host transcriptome sheds light on mechanisms of EBV carcinogenicity and provides new leads for translational applications. See related article by Chakravorty et al., p. 6010 ., (©2019 American Association for Cancer Research.)