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ACUTE LYMPHOBLASTIC LEUKEMIA

Genome-wide trans-ethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia

Leukemia volume 36, pages 865–868 (2022)Cite this article

Subjects

In a large trans-ethnic meta-analysis GWAS of childhood acute lymphoblastic leukemia (ALL), we identified three putatively novel susceptibility loci (MYB/HBS1L, TET1, and NRBF2/JMJD1C) and two additional independent risk associations at previously reported loci (CEBPE and 17q12). The known and novel ALL risk alleles together explained about 24% of familial relative risk in both non-Latino white (NLW) and Latino (LAT) populations, respectively.

Genome-wide association studies (GWAS) have identified a number of risk loci for childhood acute lymphoblastic leukemia (ALL) [1,2,3,4,5,6] and estimated the heritability to be 21% [7]. The known risk loci together account for a relatively small proportion of the total variance in genetic risk [7], suggesting that additional susceptibility alleles may be discovered. Furthermore, published GWASs predominantly investigated only European-ancestry individuals, despite the racial and ethnic disparities in ALL incidence and outcomes [8, 9].

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Fig. 1: Novel loci associated with childhood ALL in trans-ethnic meta-analysis.
Fig. 2: Polygenic Risk Score (PRS) distribution based on GWAS loci for ALL.

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Acknowledgements

This work was supported by research grants from the National Institutes of Health (R01CA155461, R01CA175737, R01ES009137, P42ES004705, P01ES018172, P42ES0470518, R24ES028524, and R35GM142783), United States. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health. The biospecimens and/or data used in this study were obtained from the California Biobank Program, (SIS request #26), Section 6555(b), 17 CCR. The California Department of Public Health is not responsible for the results or conclusions drawn by the authors of this publication. We thank Hong Quach and Diana Quach for DNA isolation support. We thank Martin Kharrazi, Robin Cooley, and Steve Graham of the California Department of Public Health for advice and logistical support. We thank Eunice Wan, Simon Wong, and Pui Yan Kwok at the UCSF Institute of Human Genetics Core for genotyping support. This study makes use of data generated by the Wellcome Trust Case–Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of the WTCCC data is available from www.wtccc.org.uk. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113 and 085475. Genotype data for COG ALL cases are available for download from dbGaP (Study Accession: phs000638.v1.p1). Data for control individuals partially came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; Schaefer and Risch, PIs) awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Northern California Community Benefit Programs. The RPGEH and the Resource for Genetic Epidemiology Research in Adult Health and Aging are described here: https://divisionofresearch.kaiserpermanente.org/genetics/rpgeh/rpgehhome. For recruitment of subjects enrolled in the CCLS replication set, the authors gratefully acknowledge the clinical investigators at the following collaborating hospitals: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Drs. Mignon Loh and Katherine Matthay), Children’s Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children’s Hospital (Dr. Gary Dahl), Children’s Hospital Oakland (Dr. James Feusner), Kaiser Permanente Roseville (formerly Sacramento) (Drs. Kent Jolly and Vincent Kiley), Kaiser Permanente Santa Clara (Drs. Carolyn Russo, Alan Wong, and Denah Taggart), Kaiser Permanente San Francisco (Dr. Kenneth Leung), and Kaiser Permanente Oakland (Drs. Daniel Kronish and Stacy Month). The authors additionally thank the families for their participation in the California Childhood Leukemia Study (formerly known as the Northern California Childhood Leukemia Study). Finally, the authors acknowledge the Center for Advanced Research Computing (CARC; https://carc.usc.edu) at the University of Southern California for providing computing resources that have contributed to the research results reported within this publication.

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Authors and Affiliations

  1. Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Soyoung Jeon, Adam J. de Smith, Shaobo Li, Minhui Chen, Tsz Fung Chan, Ivo S. Muskens, Nicholas Mancuso, Joseph L. Wiemels & Charleston W. K. Chiang

  2. Cancer Biology and Genomics Graduate Program, Program in Biological and Biomedical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Soyoung Jeon & Shaobo Li

  3. Division of Epidemiology & Biostatistics, School of Public Health, University of California, Berkeley, CA, USA

    Libby M. Morimoto & Catherine Metayer

  4. Center for Perinatal, Pediatric and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA

    Andrew T. DeWan

  5. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA

    Andrew T. DeWan & Xiaomei Ma

  6. Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA

    Nicholas Mancuso & Charleston W. K. Chiang

  7. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Nicholas Mancuso

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  1. Soyoung Jeon
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Contributions

J.L.W., C.W.K.C., and A.J.D. conceived and supervised this project; S.J., S.L., M.C., and T.C. performed data analysis; N.M., I.S.M., L.M.M., A.T.D., C.M., and X.M. provided resources; S.J., A.J.D., C.W.K.C., and J.L.W. wrote the manuscript with input from all coauthors.

Corresponding authors

Correspondence to Joseph L. Wiemels or Charleston W. K. Chiang.

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Jeon, S., de Smith, A.J., Li, S. et al. Genome-wide trans-ethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia. Leukemia 36, 865–868 (2022). https://doi.org/10.1038/s41375-021-01465-1

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