The impact of Indigenous American-like ancestry on risk of acute lymphoblastic leukemia in Hispanic/Latino children.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino children having a higher incidence of ALL than other racial/ethnic groups. Genetic variants, particularly ones found enriched in Indigenous American (IA)-like ancestry and inherited by Hispanics/Latinos, may contribute to this disparity. In this study, we characterized the impact of IA-like ancestry on overall ALL risk and the frequency and effect size of known risk alleles in a large cohort of self-reported Hispanic/Latino individuals. We also performed genome-wide admixture mapping analysis to identify potentially novel ALL risk loci. We found that global IA ancestry was positively associated with ALL risk, but the association was not significant after adjusting for socio-economic indicators. In a series of local ancestry analyses, we uncovered that at known ALL risk loci, increasing copies of the IA-like haplotype were positively and significantly associated with ALL case-control status. Further, the IA-like haplotype had ∼1.33 times the odds of harboring the risk allele compared to non-IA-like haplotypes. We found no evidence of interaction between genotype and ancestry (local or global) in relation to ALL risk. Admixture mapping identified association signals on chromosomes 2 (2q21.2), 7 (7p12.2), 10 (10q21.2), and 15 (15q22.31); however, only the variants at 7p12.2 and 10q21.2 replicated in additional cohorts. Taken together, our results suggest that increased risk of ALL in Hispanic/Latino children may be conferred by higher frequency of risk alleles within IA-like ancestry, which can be leveraged as targets of new precision health strategies and therapeutics.