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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.
Im et al. (Wed,) studied this question.