Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci.
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.
Authors
Im Im, Raduski Raduski, Mills Mills, Bhattarai Bhattarai, Mobley Mobley, Barnett Barnett, Lu Lu, Liao Liao, Anderson Anderson, Johnson Johnson, Langer Langer, Hooten Hooten, Seif Seif, Bernt Bernt, Tsang Tsang, Mamou Mamou, Gil-de-Gómez Gil-de-Gómez, Wolfson Wolfson, Friedman Friedman, Shukla Shukla, Klesse Klesse, Marcotte Marcotte, Ji Ji, Dang Dang, Luo Luo, Zhong Zhong, Langie Langie, Chiang Chiang, de Smith de Smith, Wiemels Wiemels, DeWan DeWan, Ma Ma, Metayer Metayer, Wang Wang, Nelson Nelson, Pankratz Pankratz, Yang Yang, Basu Basu, Turcotte Turcotte, Yang Yang, Savic Savic, Scheurer Scheurer, Spector Spector
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