Findings indicate associations of acute lymphoblastic leukemia (ALL) molecular subtypes and prognosis with genetic ancestry, potentially suggesting a genetic basis for some of the racial and ethnic disparities in ALL. Thus, molecular subtype–driven treatment individualization is required to help address racial and ethnic gaps in results.

• In this genetic association study, the molecular subtypes of ALL were comprehensively analyzed among 2,428 patients from racially and ethnically diverse populations, and differences in leukemia somatic genomics across ancestries were reported.

• Overall 21 ALL subtypes were found, of which 8 were identified to be linked with ancestry.

• A positive association of East Asian ancestry with the frequency of somatic DUX4 and ZNF384 gene rearrangements and a negative association with BCR-ABL1–like ALL and T-cell ALL was found.

• By contrast, occurrence of CRLF2 rearrangements was found to be linked with Native American ancestry (odds ratio [OR], 1.48).

• In children of African descent, a marked preponderance of T-cell ALL was present than those with a high percentage of Native American ancestry (African: OR, 1.22; Native American: OR, 0.53).

• As continuous variables, African and Native American ancestries were both found to be linked with poorer event-free survival (for every 25% increase in ancestry: hazard ratio [HR] 1.2 for African ancestry; HR, 1.3 for Native American ancestry) as well as overall survival (for every 25% increase in ancestry: HR, 1.2 for African ancestry; HR, 1.4 for Native American ancestry).

• Native American and African ancestries continued to be linked with poor prognosis even post-adjustment of biological subtypes and clinical features.