Im C, Raduski AR, Mills LJ, Bhattarai KR, Mobley RJ, Barnett KR, Lu Z, Liao K, Anderson N, Johnson RA, Langer E, Hooten AJ, Seif AE, Bernt KM, Tsang M, Mamou BA, Gil-de-Gómez L, Wolfson JA, Friedman DN, Shukla N, Klesse LJ, Marcotte EL, Ji L, Dang A, Luo M, Zhong Y, Langie J, Chiang CWK, de Smith A, Wiemels JL, DeWan A, Ma X, Metayer C, Wang Z, Nelson HH, Pankratz N, Yang T, Basu S, Turcotte LM, Yang JJ, Savic D, Scheurer ME, Spector LG. Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci. Nat Commun. 2025 Oct 22;16(1):8974. doi: 10.1038/s41467-025-64337-7. PMID: 41125582; PMCID: PMC12546916.
Study ID Citation
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.