Abstract Introduction: AML is a relatively rare pediatric hematological malignancy, but its treatment outcomes trail other acute leukemias with a 5-year survival rate at ∼70%. While genome-scale susceptibility studies of adult AML risk have been conducted, similar pediatric AML studies have not been published. Methods: 1854 pediatric AML cases (diagnosis age 25y) were assembled from the Children’s Oncology Group (clinical trials AAML-03P1/0531/1031), Hospital for Sick Children (CA), International Berlin-Frankfurt-Münster Study Group (DE), and Royal Alexandra Hospital for Children (AUS). Cases were genotyped with the Illumina HumanOmni 2.5 BeadChip. Using ADMIXTURE-inferred global genetic ancestry, 1355 cases were grouped in African (AFR, N=95), Admixed American (AMR, N=118), East Asian (EAS, N=74) and European (EUR, N=1068) ancestry groups. Sex-/ancestry-matched publicly available adult controls from 3 external cohorts (Age-Related Eye Disease Study, Health and Retirement Study, Long Life Family Study) genotyped with the same platform were identified at a ∼4:1 ratio. TOPMed-based imputation (version r3) supported ancestry-specific GWAS with 5.5-10.7 million common variants (minor allele frequency, MAF≥1%). Logistic regression models adjusted for population substructure tested variant risk associations. Multi-ancestry meta-analysis was performed using an inverse variance-weighted fixed effects model. Results: Four novel genome-wide significant (P5x10-8) pediatric AML risk loci (PRIM2, HERC2, AGRN, DEFB131A) were identified in the EUR GWAS (N=5340), with moderate per-allele odd ratios (OR range: 1.9-2.9). In silico analyses indicated lead variants at HERC2, AGRN, and DEFB131A loci are in active chromatin regions in blood or bone marrow tissues and overlap transcription factor binding sites, including in leukemia cell lines. The HERC2 index variant (OR=1.9, 95% CI: 1.5-2.3) is associated with HERC2 expression in venous blood (GTEx). Multiple variants at known EUR adult AML risk locus KMT5B were also nominally replicated (P=8.7x10-3). Additional suggestive associations (P1x10-6) in the AFR (N=475) and AMR (N=518) GWAS were seen; among these, putative pediatric AML risk locus KANK1, which was characterized by low frequency (MAF=1-5%) AFR-specific effect alleles, i.e., nearly absent in other ancestries, is notable for its large risk effects (OR=5.6, 95% CI: 3.0-10.7). The multi-ancestry meta-analysis did not reveal additional genetic signals shared across ancestry groups. Conclusion: We report results from the first pediatric AML GWAS (N=6507, 1355 cases) using international data. We identified 4 novel EUR-specific risk loci, a plausible novel AFR-specific risk locus, and replicated KMT5B, a risk locus reported in a EUR adult AML meta-analysis. Future work includes replication and functional validation studies. Citation Format: Cindy Im, Lauren J. Mills, Peggy Meng, Marijana Vujkovic, Jenny N. Poynter, Melissa Maria Hudson, Kirsten K. Ness, Joseph L. Wiemels, Logan G. Spector, Saonli Basu, Zhaoming Wang, Richard Aplenc. Multi-ancestry genome-wide association study (GWAS) of pediatric acute myeloid leukemia (AML) risk identifies four risk loci abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7892.
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