Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci
- 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
2025-10-22
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.