Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-22 DOI:10.1038/s41467-025-64337-7

Cindy Im,Andrew R Raduski,Lauren J Mills,Kashi Raj Bhattarai,Robert J Mobley,Kelly R Barnett,Zhanni Lu,Kenneth Liao,Nathan Anderson,Rebecca A Johnson,Erica Langer,Anthony J Hooten,Alix E Seif,Kathrin M Bernt,Matthew Tsang,Brandon A Mamou,Luis Gil-de-Gómez,Julie A Wolfson,Danielle N Friedman,Neerav Shukla,Laura J Klesse,Erin L Marcotte,Lingyun Ji,Alice Dang,Minjie Luo,Yiming Zhong,Jalen Langie,Charleston W K Chiang,Adam de Smith,Joseph L Wiemels,Andrew DeWan,Xiaomei Ma,Catherine Metayer,Zhaoming Wang,Heather H Nelson,Nathan Pankratz,Tianzhong Yang,Saonli Basu,Lucie M Turcotte,Jun J Yang,Daniel Savic,Michael E Scheurer,Logan G Spector

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Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P < 5 × 10-8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10-3). Novel risk variants were also associated with subtype-specific disease (P < 0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower susceptibility for a subtype with excellent prognosis (ETV6-RUNX1). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity (P < 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.

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儿童b细胞急性淋巴细胞白血病的全基因组关联研究揭示了新的非洲血统特异性易感位点。

b细胞急性淋巴细胞白血病（B-ALL）是儿童最常见的恶性肿瘤。鉴于种族/民族在发病率和结果上的差异，需要在非洲血统儿童中进行B-ALL全基因组关联研究。利用840名患有B-ALL的非洲裔美国儿童和3360名对照的多机构数据集，经荟萃分析，9个位点达到全基因组显著性（P < 5 × 10-8）。两个基因座被建立为跨祖先易感区（IKZF1, ARID5B），而其余的新基因座是非洲人群特有的。携带新型风险等位基因的儿童的5年总生存率明显较差（83%对96%，P = 4.8 × 10-3）。新的风险变异也与亚型特异性疾病相关（P < 0.05），包括非洲裔美国儿童中代表性过高的亚型（TCF3-PBX1）的易感性较高，以及预后良好的亚型（ETV6-RUNX1）的易感性较低。功能实验显示，新的B-ALL危险变异在b细胞和白血病细胞系中具有等位基因特异性的转录活性差异（P < 0.05）。这些发现揭示了白血病发生和预后的血统相关差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.