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A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.
de Smith, Adam J; Wahlster, Lara; Jeon, Soyoung; Kachuri, Linda; Black, Susan; Langie, Jalen; Cato, Liam D; Nakatsuka, Nathan; Chan, Tsz-Fung; Xia, Guangze; Mazumder, Soumyaa; Yang, Wenjian; Gazal, Steven; Eng, Celeste; Hu, Donglei; Burchard, Esteban González; Ziv, Elad; Metayer, Catherine; Mancuso, Nicholas; Yang, Jun J; Ma, Xiaomei; Wiemels, Joseph L; Yu, Fulong; Chiang, Charleston W K; Sankaran, Vijay G.
Afiliação
  • 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: desm
  • 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, US
  • 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, US
  • 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
  • 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.
Cell Genom ; 4(4): 100526, 2024 Apr 10.
Article em En | MEDLINE | ID: mdl-38537633
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Leucemia-Linfoma Linfoblástico de Células Precursoras Limite: Child / Humans Idioma: En Revista: Cell Genom Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Leucemia-Linfoma Linfoblástico de Células Precursoras Limite: Child / Humans Idioma: En Revista: Cell Genom Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos