Genetic ancestry, differential gene expression, and survival in pediatric B‐cell acute lymphoblastic leukemia

BACKGROUND: Black children have lower incidence yet worse survival than White and Latinx children with B‐cell acute lymphoblastic leukemia (B‐ALL). It is unclear how reported race/ethnicity (RRE) is associated with death in B‐ALL after accounting for differentially expressed genes associated with genetic ancestry. METHODS: Using Phase 1 and 2 NCI TARGET B‐ALL cases (N = 273; RRE‐Black = 21, RRE‐White = 162, RRE‐Latinx = 69, RRE‐Other = 9, RRE‐Unknown = 12), we estimated proportions of African (AFR), European (EUR), and Amerindian (AMR) genetic ancestry. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) between ancestry and death while adjusting for RRE and clinical measures. We identified genes associated with genetic ancestry and adjusted for them in RRE and death associations. RESULTS: Genetic ancestry varied within RRE (RRE‐Black, AFR proportion: Mean: 78.5%, Range: 38.2%–93.6%; RRE‐White, EUR proportion: Mean: 94%, Range: 1.6%–99.9%; RRE‐Latinx, AMR proportion: Mean: 52.0%, Range: 1.2%–98.7%). We identified 10, 1, and 6 differentially expressed genes (p (adjusted) <0.05) associated with AFR, AMR, and EUR ancestry proportion, respectively. We found AMR and AFR ancestry were statistically significantly associated with death (AMR each 10% HR: 1.05, 95% CI: 1.03–1.17, AFR each 10% increase HR: 1.03, 95% CI:1.01–1.19). RRE differences in the risk of death were larger in magnitude upon adjustment for genes associated with genetic ancestry for RRE‐Black, but not RRE‐Latinx children (RRE‐Black HR: 3.35, 95% CI: 1.31, 8.53; RRE‐Latinx HR: 1.47, 0.88–2.45). CONCLUSIONS: Our work highlights B‐ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.