ALL-031: The Impact of Genetic Ancestry on the Biology and Prognosis of Childhood Acute Lymphoblastic Leukemia

Context: Although cure rates of childhood acute lymphoblastic leukemia (ALL) have improved with risk-adapted therapy, stark racial disparities persist in both the incidence and treatment outcomes of ALL. There is a paucity of data describing the genetic basis of these disparities, especially in relation to modern ALL molecular taxonomy and in the context of contemporary treatment regimens. Objective: Determine the associations of genetic ancestry with ALL biology and the relevance of genetic ancestry to survival outcomes of modern ALL therapy. Design: This was a multi-national genomic study of 2,428 children with ALL in front-line trials from the United States, Singapore, Malaysia, and Guatemala, representing diverse populations of European, African, Native American, East Asian, and South Asian descent. We performed RNA sequencing to characterize ALL molecular subtype and genetic ancestry and then evaluated associations of genetic ancestries with ALL biology and treatment outcomes. Results: Of 21 ALL subtypes, 11 showed significant associations with ancestry. The frequency of somatic DUX4 gene rearrangement was positively correlated with both East Asian and South Asian ancestries, and alterations in ZNF384 and PAX5 increased with East Asian ancestry. By contrast, occurrence of CRLF2 rearrangements was linked to Native American ancestry. ETV6-RUNX1 fusion became less frequent as Native American ancestry increased, with the opposite observed for ETV6-RUNX1-like. There was a marked preponderance of T-ALL in children of African descent. African ancestry was also positively correlated with the prevalence of TCF3-PBX1 and MEF2D fusions. Survival outcomes differed significantly by genetic ancestry, where African and Native American ancestries were both associated with poorer event-free survival (African: HR, 2.3; 95% CI, 1.4–3.8; P=0.001; Native American: HR, 2.5; 95% CI, 1.0–5.9; P=0.044) and overall survival (African: HR, 2·4; 95% CI, 1.2-4.7; P=0.012 for African; Native American: HR, 3.3; 95% CI, 1.1-10.0; P=0.033). Importantly, even after adjusting for biological subtypes and clinical features, Native American and African ancestries remained independently associated with poor prognosis. Conclusions: ALL biology and prognosis are highly associated with genetic ancestry, pointing to a genetic basis for racial disparities in ALL. Biology-driven treatment individualization is needed to eliminate racial gaps in outcomes.