The genetic makeup of Hispanic/Latino populations reflects varying contributions from Indigenous American, European, and African ancestry, shaped by the complex demographic history of Latin America. Previous studies have suggested that higher Indigenous American–related ancestry might increase the risk of acute lymphoblastic leukemia (ALL), potentially explaining the higher incidence of ALL among Hispanic/Latino children compared with other pediatric populations in the United States. Although genome-wide association studies (GWAS) have demonstrated that ALL has a measurable inherited component, the relationship between genetic ancestry and ALL risk remains complex. Environmental and socioeconomic factors, which also contribute to disparities in disease incidence, may confound ancestry-based associations.
To address these limitations, a recent large multi-cohort genetic study led by researchers at the University of Southern California sought to disentangle the relationships between ALL risk, genetic ancestry, and socioeconomic factors. The investigators analyzed genetic data from thousands of Hispanic/Latino children using a study design that explicitly accounted for socioeconomic indicators. They examined both global genetic ancestry across the genome and local ancestry at established ALL susceptibility loci. Additionally, the researchers applied admixture mapping to identify ancestry-associated risk regions.
After adjustment for socioeconomic factors, global Indigenous American–related ancestry was no longer linked with ALL risk, suggesting that previously reported associations were largely driven by non-genetic influences. Nonetheless, the study identified clear genetic signals at specific genomic regions already known to influence ALL susceptibility. At these loci, leukemia-associated variants were more frequently observed on Indigenous American–derived genomic segments than on European- or African-derived segments. Furthermore, the investigators found no evidence that these risk variants exert stronger biological effects in Indigenous American ancestry backgrounds. Instead, the variants conferred similar increases in leukemia risk regardless of ancestry, with observed differences in incidence reflecting variation in allele frequencies rather than differences in biological impact.
Overall, these findings demonstrate that the higher incidence of ALL among Hispanic/Latino children is not driven by Indigenous American ancestry itself, but rather by differences in the frequency of established genetic risk variants. By accounting for socioeconomic factors and focusing on local rather than global ancestry, the study provides valuable insights for future researchers assessing the risks of childhood cancers. This work highlights the complex etiological basis of ALL across populations and underscores the importance of ancestry-informed genetic analyses as well as the inclusion of diverse populations in genetic research.
Citation:
Article Title: The impact of Indigenous American-like ancestry on the risk of acute lymphoblastic leukemia in Hispanic/Latino children
Authors: Langie J, Chan TF, Yang W, Kang AY, Morimoto L, Stram DO, Mancuso N, Ma X, Metayer C, Lupo PJ, Rabin KR, Scheurer ME, Wiemels JL, Yang JJ, de Smith AJ, Chiang CWK.
Published In: HGG Adv. 2026 Jan 15; 7(1):100534. doi: 10.1016/j.xhgg.2025.100534.