Abstract:
Burkitt lymphoma (BL) is a B-cell malignancy that disproportionately affects children in sub-Saharan Africa. We performed a
genome-wide association study (GWAS) in a combined set of 800 childhood cases and 3865 controls in East Africa, controlling for
age, sex, country, population-specific principal components, and a genetic relationship matrix. This analysis identified a BLprotective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR] = 0.57; p = 5.7 × 10−9
). The
results were robust in standard meta-analysis (OR = 0.57, p < 1.6 × 10−8
), sensitivity analyses (removing genomic outliers and
related individuals), and after adjustment for Epstein-Barr virus (EBV) status. Genomic analyses revealed long-range (over ~700 kb)
chromatin interactions between the chr21q22.12 locus and the RUNX1-P1 promoter region. The African-specific rs2242780-C allele
(r
2 = 0.69 with the rs111457485-T allele in the study controls) showed increased enhancer activity in in-vitro Luciferase reporter
assays (p = 4.5 × 10−10), nominating it as the likely functional variant for the BL-associated loci. In addition to the association with
reduced BL risk in GWAS (OR = 0.62, p = 2.24 × 10−8
), the rs2242780-C allele was also associated with better survival in patients
with abdominal-only BL in exploratory analyses (hazard ratio = 0.39, p = 0.038, 106 patients, 59 deaths). Our GWAS uncovered
novel BL-protective loci near RUNX1, offering insights into the genetic etiology of BL in African children.
