Genome‐wide association study of childhood burkitt lymphoma in east africa identifies a novel germline susceptibility locus on chromosome 21

Introduction: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with hallmark somatic IG::MYC chromosomal translocations. BL is responsible for a significant proportion of childhood cancers in equatorial Africa, where exposure to Epstein Barr Virus (EBV) and P. falciparum are established risk factors. Host genetic factors are suspected to modify risk but are currently undefined, with exception of the sickle cell trait that is protective against severe malaria and childhood BL in Africa. Discovery of novel host genetic susceptibility in BL would suggest new directions to understand the biology of BL, particularly the link between host and environmental cofactors. Methods: We conducted the first genome-wide association study (GWAS) of BL among 4,645 children (800 with BL) aged 0–15 years enrolled in the Epidemiology of Burkitt lymphoma in East African Children and Minors (EMBLEM) study in Uganda, Kenya, and Tanzania (2010–2016) and the Childhood Infections and Cancer case-control study in Malawi (2005–2008). Genotypes at approximately 4.6 million sites were determined using the Infinium Omni5Exome-4 v1.3 BeadChip (Illumina) and imputation was performed using the African Genome Resources reference panel (Sanger Imputation Service), with rigorous quality control to filter unreliable calls. GWAS based on logistic mixed model was performed in SAIGE, adjusting for age, sex, and ancestry using population-specific principal components, and country of origin. Additional analyses were performed using genomic, epigenomic and expression data from the BL and ICGC MMML-Seq genome sequencing projects to provide insight into the potential mechanisms by which the novel loci may influence BL risk in African children. Results: Considering variants with a minor allele frequency threshold of ≥5%, we identified one genome-wide significant locus at 21q22.12 (Figure 1A) upstream of RUNX1. The index SNP (rs111457485, ref/effect: C/T, effect size: −0.57; p-value = 5.7 × 10−9; Figure 1B) is common in Africans (frequency of allele T: 10.2%) and rare in Europeans (allele frequency of T: 0.7%) in the 1000 Genomes populations. Fine mapping in this locus using the Sum of Single Effects (SuSiE) model revealed a credible set of 17 variants spanning 76 kb including the causal variant at the locus with 95% probability (Figure 1C). This associated region contains enhancer elements linked to RUNX1 expression that are differentially methylated in BL as compared to follicular lymphoma. Moreover, mining of RNA-seq data identified a novel spliced transcript expressed in BL and germinal center B cells. In secondary transcriptome-wide analyses in whole blood and spleen, we identified statistically significant association with additional loci at 19p13.2 in region previously identified to harbor somatic mutations in BL. The research was funded by: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cancer Health Disparities, Genomics, Epigenomics, and Other-Omics No conflicts of interests pertinent to the abstract.