Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia

• Published in: Nature genetics Vol. 56; no. 11; pp. 2434 - 2446
• Main Authors: Stiff, Andrew, Fornerod, Maarten, Kain, Bailee N., Nicolet, Deedra, Kelly, Benjamin J., Miller, Katherine E., Mrózek, Krzysztof, Boateng, Isaiah, Bollas, Audrey, Garfinkle, Elizabeth A. R., Momoh, Omolegho, Fasola, Foluke A., Olawumi, Hannah O., Mencia-Trinchant, Nuria, Kloppers, Jean F., van Marle, Anne-Cecilia, Hu, Eileen, Wijeratne, Saranga, Wheeler, Gregory, Walker, Christopher J., Buss, Jill, Heyrosa, Adrienne, Desai, Helee, Laganson, Andrea, Hamp, Ethan, Abu-Shihab, Yazan, Abaza, Hasan, Kronen, Parker, Sen, Sidharth, Johnstone, Megan E., Quinn, Kate, Wronowski, Ben, Hertlein, Erin, Miles, Linde A., Mims, Alice S., Oakes, Christopher C., Blachly, James S., Larkin, Karilyn T., Mundy-Bosse, Bethany, Carroll, Andrew J., Powell, Bayard L., Kolitz, Jonathan E., Stone, Richard M., Duarte, Cassandra, Abbott, Diana, Amaya, Maria L., Jordan, Craig T., Uy, Geoffrey L., Stock, Wendy, Archer, Kellie J., Paskett, Electra D., Guzman, Monica L., Levine, Ross L., Menghrajani, Kamal, Chakravarty, Debyani, Berger, Michael F., Bottomly, Daniel, McWeeney, Shannon K., Tyner, Jeffrey W., Byrd, John C., Salomonis, Nathan, Grimes, H. Leighton, Mardis, Elaine R., Eisfeld, Ann-Kathrin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2024; Nature Publishing Group
• Subjects: 38; 38/39; 38/91; 45/23; 45/77; 692/308/2056; 692/308/409; 692/308/575; Acute myeloid leukemia; Adult; Aged; Agriculture; Animal Genetics and Genomics; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Black or African American - genetics; Cancer; Cancer Research; Cell survival; Female; Gene Expression Profiling; Gene Function; Genes; Genomics; GTP Phosphohydrolases - genetics; Health risk assessment; Human Genetics; Humans; Isocitrate Dehydrogenase - genetics; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Male; Membrane Proteins - genetics; Middle Aged; Mutation; Myelodysplastic syndrome; Nuclear Proteins - genetics; Nucleophosmin; Patients; Point mutation; Prognosis; Risk; Self report; Survival; Transcriptome; Transcriptomes; White - genetics
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-024-01929-x

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction. Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.