Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia
Andrew Stiff, Maarten Fornerod, Bailee Kain, Deedra Nicolet, Benjamin Kelly, Katherine Miller, Krzysztof Mrózek, Isaiah Boateng, Audrey Bollas, Elizabeth A.R. Garfinkle, O. M. Momoh, Foluke Fasola, H.O. Olawumi, Nuria Mencia-Trinchant, Jean F. Kloppers, Anne‐Cecilia van Marle, Eileen Hu, Saranga Wijeratne, Gregory Wheeler, Christopher J. Walker, Jill Buss, Adrienne Heyrosa, Helee Desai, Andrea Laganson, Ethan Hamp, Yazan Abu-Shihab, Hasan Abaza, Parker Kronen, Sidharth Sen, Megan Johnstone, K. R. Quinn, Ben Wronowski, Erin Hertlein, Linde A. Miles, Alice S. Mims, Christopher C. Oakes, James S. Blachly, Karilyn Larkin, Bethany L. Mundy-Bosse, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard M. Stone, Cassandra Duarte, Diana Abbott, Maria L. Amaya, Craig T. Jordan, Geoffrey L. Uy, Wendy Stock, Kellie J. Archer, Electra D. Paskett, Monica L. Guzman, Ross L. Levine, Kamal Menghrajani, Debyani Chakravarty, Michael F. Berger, Daniel Bottomly, Shannon K. McWeeney, Jeffrey Tyner, John C. Byrd, Nathan Salomonis, H. Leighton Grimes, Elaine R. Mardis, Ann‐Kathrin Eisfeld
Abstract
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.