Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

Austin L. Brown, Adam J. De Smith, Vincent U. Gant, Wenjian Yang, Michael E. Scheurer, Kyle M. Walsh, Jonathan M. Chernus, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Naomi Winick, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Eleanor Feingold, Meenakshi DevidasLisa F. Barcellos, Helen M. Hansen, Libby Morimoto, Alice Y. Kang, Ivan Smirnov, Jasmine Healy, Caroline Laverdie`re, Daniel Sinnett, Jeffrey W. Taub, Jillian M. Birch, Pamela Thompson, Logan G. Spector, Maria S. Pombo-De-Oliveira, Andrew T. DeWan, Charles G. Mullighan, Stephen P. Hunger, Ching Hon Pui, Mignon L. Loh, Michael E. Zwick, Catherine Metayer, Xiaomei Ma, Beth A. Mueller, Stephanie L. Sherman, Joseph L. Wiemels, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta 5 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta 5 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta 58.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta 54.1 × 10-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Original languageEnglish (US)
Pages (from-to)1227-1237
Number of pages11
JournalBlood
Volume134
Issue number15
DOIs
StatePublished - Oct 10 2019

Bibliographical note

Funding Information:
1Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX; 2Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA; 3Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA; 4Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN; 5Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC; 6Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; 7Avera Institute for Human Genetics, Sioux Falls, SD; 8Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; 9Department of Pathology, The Ohio State University, Columbus, OH; 10Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; 11Department of Pathology and 12Department of Oncology, Johns Hopkins Hospital, Baltimore, MD;13Department of Pathology and 14Department of Medicine, University of Washington Medical Center, Seattle, WA; 15Department of Pediatrics, Perlmutter Cancer Center, New York University, New York, NY; 16Department of Biostatistics, College of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL; 17Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA; 18Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA; 19Division of Hematology-Oncology, Sainte-Justine University Health Center, Montreal, QC, Canada; 20Division of Hematology Oncology, Department of Oncology, Wayne State University, Detroit, MI; 21Department of Paediatric and Adolescent Oncology, University of Manchester, Manchester, United Kingdom; 22Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN; 23Pediatric Hematology-Oncology Program, Instituto Nacional de Cancer, Rio de Janeiro, Brazil; 24Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT; 25Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN; 26Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA; 27Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN; 28Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA; 29Department of Human Genetics, Emory University, Atlanta, GA; and 30Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA

Funding Information:
This work was supported by grant RP170074 from the Cancer Prevention and Research Institute of Texas (K.R.R. and P.J.L.) and by funds from the Jeffrey Pride Foundation and the COG Foundation (K.R.R.). Work was also supported in part by the National Institutes of Health National Cancer Institute (NCI) (grant K07 CA218362 to A.L.B.). Flow cytometry assays were performed at the Research Flow Cytometry Core Facility of Texas Children’s Cancer and Hematology Centers with the support from the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NCI (cancer center support grant P30CA125123). The work of St. Jude investigators is supported by NCI grants CA21765 and P50 GM115279 and the American Lebanese Syrian Associated Charities. The work of COG investigators was supported by the National Institutes of Health NCI (grants U10 CA 29139, U10 CA98543, U10 CA98413, U10 CA180886, and U10 CA180899 to the COG) and supported by St. Baldrick’s Foundation. S.P.H. is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics at The Children’s Hospital of Philadelphia. The IS-DSAL study was supported by Alex’s Lemonade Stand Foundation “A” Awards (A.J.d.S. and K.M.W.), the Emerging Investigator Fellowship Grant from the Pediatric Cancer Research Foundation (A.J.d.S.), The Children’s Health and Discovery Initiative of Translating Duke Health (K.M.W.), and the National Institutes of Health NCI (research grants R01 CA155461 to J.L.W. and X.M.) and National Institute of Environmental Health Sciences (R01 ES009137 to C.M., P24 ES004705 to C.M., and R24 ES028524 to C.M. and L.M.). The 2016-2019 Childhood Leukemia International Consortium Scientific Annual Meetings were supported in part by the National Institutes of Health, National Institute of Environmental Health Sciences (award number U13 ES026496).

Funding Information:
The IS-DSAL study included biospecimens and/or data obtained from the California Biobank Program (screening information system requests 26 and 572), Section 6555(b), 17 California code of regulations. The California Department of Public Health is not responsible for the results or conclusions drawn by the authors of this publication. The collection of cancer incidence data used in the CCRLP study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885, Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries, under cooperative agreement 5NU58DP003862-04/DP003862, 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. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Institutes of Health, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors. This study used birth data obtained from the State of California Center for Health Statistics and Informatics. The California Department of Public Health is not responsible for the analyses, interpretations, or conclusions drawn by the authors regarding the birth data used in this publication.

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