A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.

Autor:	de Smith AJ; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: desmith@usc.edu., Wahlster L; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Jeon S; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Kachuri L; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA., Black S; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Langie J; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Cato LD; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Nakatsuka N; New York Genome Center, New York, NY 10013, USA., Chan TF; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Xia G; GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China., Mazumder S; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Yang W; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Gazal S; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Eng C; Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Biotherapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA., Hu D; Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Burchard EG; Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Biotherapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA., Ziv E; Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Metayer C; School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA., Mancuso N; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Yang JJ; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Ma X; Yale School of Public Health, New Haven, CT 06520, USA., Wiemels JL; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Yu F; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China., Chiang CWK; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Sankaran VG; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: sankaran@broadinstitute.org.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2024 Apr 10; Vol. 4 (4), pp. 100526. Date of Electronic Publication: 2024 Mar 26.
DOI:	10.1016/j.xgen.2024.100526
Abstrakt:	Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children. Competing Interests: Declaration of interests V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, and Cellarity, all unrelated to the present work. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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