一项全基因组关联研究确定了位于21号染色体22.12区域的一个非洲特异性基因座，该基因座与伯基特淋巴瘤的风险和生存相关。

A genome-wide association study identifies an African-specific locus on chromosome 21q22.12 associated with Burkitt lymphoma risk and survival.

作者信息

Dutta Diptavo, Gouveia Mateus H, Gorman Bryan R, Adu-Gyamfi Atuahene, Lee Chia-Han, Ogwang Martin D, Kerchan Patrick, Reynolds Steven J, Tenge Constance N, Were Pamela A, Wekesa Walter N, Tenge Robert K, Masalu Nestory, Kawira Esther L, Kinyera Tobias, Otim Isaac, Nabalende Hadijah, Dhudha Herry, Candia Bosco, Abaru Janet, Yan Wusheng, Florez-Vargas Oscar, Xie Yi, Ho Michelle, Ayers Leona W, Bhatia Kishor, Goedert James J, Pfeiffer Ruth M, Manning Michelle, Hutchinson Amy, Cole Nathan, Luo Wen, Hicks Belynda, Chagaluka George, Johnston W Thomas, Mutalima Nora, Borgstein Eric, Liomba George N, Kamiza Steven, Mkandawire Nyengo, Molyneux Elizabeth M, Mitambo Collins, Newton Robert, Siebert Reiner, Dean Michael, Yeager Meredith, Chanock Stephen J, Prokunina-Olsson Ludmila, Mbulaiteye Sam M

机构信息

Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, MD, USA.

Center for Research on Genomics & Global Health, Division of Intramural Research, National Human Genome Research Institute, Bethesda, MD, USA.

出版信息

Leukemia. 2025 Jul 11. doi: 10.1038/s41375-025-02690-8.

DOI:10.1038/s41375-025-02690-8

PMID:40646133

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 BL-protective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR] = 0.57; p = 5.7 × 10). The results were robust in standard meta-analysis (OR = 0.57, p < 1.6 × 10), 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 = 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), 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), 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.

摘要

伯基特淋巴瘤（BL）是一种B细胞恶性肿瘤，在撒哈拉以南非洲地区对儿童的影响尤为严重。我们在东非的800例儿童病例和3865例对照的组合样本中进行了全基因组关联研究（GWAS），对年龄、性别、国家、特定人群主成分以及遗传关系矩阵进行了控制。该分析在21号染色体22.12区域内确定了一个由rs111457485 - T等位基因标记的BL保护区域（优势比[OR]=0.57；p = 5.7×10）。在标准荟萃分析（OR = 0.57，p < 1.6×10）、敏感性分析（去除基因组异常值和相关个体）以及调整爱泼斯坦 - 巴尔病毒（EBV）状态后，结果依然稳健。基因组分析揭示了21号染色体22.12位点与RUNX1 - P1启动子区域之间的长程（超过约700kb）染色质相互作用。非洲特有的rs2242780 - C等位基因（在研究对照中与rs111457485 - T等位基因的r = 0.69）在体外荧光素酶报告基因检测中显示增强子活性增加（p = 4.5×10），表明它可能是与BL相关位点的功能变异。除了在GWAS中与降低BL风险相关（OR = 0.62，p = 2.24×10）外，在探索性分析中，rs2242780 - C等位基因还与仅腹部BL患者的更好生存相关（风险比 = 0.39，p = 0.038，106例患者，59例死亡）。我们的GWAS在RUNX1附近发现了新的BL保护位点，为非洲儿童BL的遗传病因提供了见解。