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<p>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 (<i>P</i> &lt; 5 × 10<sup>−8</sup>) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (<i>IKZF1</i>, <i>ARID5B</i>), 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, <i>P</i> = 4.8 × 10<sup>−3</sup>). Novel risk variants were also associated with subtype-specific disease (<i>P</i> &lt; 0.05), including higher susceptibility for a subtype overrepresented in African American children (<i>TCF3-PBX1</i>) and lower susceptibility for a subtype with excellent prognosis (<i>ETV6-RUNX1</i>). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity (<i>P</i> &lt; 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • 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

摘要

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.