Abstract LB387: Genome-wide association study identifies germline susceptibility loci for acute myeloid leukemia

Abstract Background: Prior genome-wide association studies (GWAS) of acute myeloid leukemia (AML) have been limited by sample size and ancestry representation. We conducted the largest multi-ancestry GWAS to-date to identify germline susceptibility loci associated with AML. Methods: The study is part of the NCI-CIBMTR® collaborative Genomic Studies in Blood and Marrow Transplantation (GS-BMT) project. Patients with AML were allogeneic hematopoietic cell transplantation (HCT) recipients with blood samples collected before HCT (82% were in complete morphologic remission). AML-free controls included HCT donors from GS-BMT and participants from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Samples were genotyped on Illumina Global Screening Array platforms, imputed to the TOPMed v3 reference panel, and analyzed using REGENIE v4.1 under an additive model with Firth-approximate likelihood ratio tests. Models were adjusted for sex, age, and genetic principal components. Variants with imputation quality score > 0.2 and minor allele count ≥ 30 were tested. Results: The primary analysis included 10,937 cases and 100,705 controls spanning multiple genetically inferred ancestry groups, including 1,776 cases of non-European ancestry. Test statistic inflation was limited (λ1,000=1.001; LDSCR intercept=1.014), indicating minimal residual confounding. We observed eight genomic regions with genome-wide significant associations. Among these, we highlight three signals on chromosome 5, including rs141601766 at 5q35 (OR = 22.79, 95% CI = 14.34-36.20, P = 1.05×10-40), a rare non-synonymous variant in DDX41 classified as pathogenic or likely pathogenic in ClinVar and previously implicated in familial AML predisposition; rs552806293 at 5q35 (OR = 22.97, 95% CI = 13.26-39.80, P = 1.03×10-28), a rare intronic variant within UIMC1, a gene with established roles in DNA damage response; and rs7705526 at 5p15 (TERT locus; OR = 1.18, 95% CI = 1.15-1.22, P = 6.65×10-25), a common variant previously associated with leukocyte telomere length, clonal hematopoiesis, myeloproliferative neoplasms, hematologic quantitative traits, and ovarian serous carcinoma in large GWAS. Conditional analyses suggested the two 5q35 signals were statistically independent. Conclusions: This multi-ancestry GWAS identifies multiple germline susceptibility loci for AML risk. Ongoing work includes ancestry-specific, molecular-stratification, and outcome analyses. Citation Format: Xueyao Wu, Filip Pirsl, Gabrielle Schmidt, Maryam Rafati, Aurélie Vogt, Herbert Higson, Jia Liu, Jiahui Wang, Shilpa Gaddam, Shengchao Li, Wael Saber, Yung-Tsi Bolon, Steven Moore, Sharon A. Savage, Stephen Chanock, Stephen Spellman, Peter Kraft, Shahinaz M. Gadalla. Genome-wide association study identifies germline susceptibility loci for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB387.