Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome–positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 × 10−14, odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 × 10−8, OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.

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We thank the patients and parents who participated in the COG protocols included in this study, the clinicians and research staff at COG institutions and J. Pullen (University of Mississippi at Jackson) for assistance in the classification of patients with ALL. Genome-wide genotyping of COG P9905 samples was performed by the Center for Molecular Medicine with generous financial support from the Jeffrey Pride Foundation and the National Childhood Cancer Foundation. V.P.-A. is supported by a Spanish Ministry of Education Fellowship Grant and by a St. Jude Children's Research Hospital Academic Programs Special Fellowship. J.J.Y. is supported by an American Society of Hematology Scholar Award, an Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant and by the Order of St. Francis Foundation. K.G.R. is supported by a National Health and Medical Research Council (Australia) Overseas Training Fellowship and by a Haematology Society of Australia and New Zealand Novartis New Investigator Scholarship. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. We thank M. Shriver (Pennsylvania State University) for sharing SNP genotype data for the Native American references, J. Pritchard and J. Degner (University of Chicago) for sharing DNase I hypersensitivity data for HapMap YRI cell lines, R.C. Ribeiro (St. Jude Children's Research Hospital) and P. De Alarcon (University of Illinois College of Medicine at Peoria) for coordinating collaborations in Guatemala and S. Naron for her editorial assistance. This work was supported by the US National Institutes of Health (grant numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729 and GM92666), in part by the intramural Program of the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). Study sponsors were not directly involved in the design of the study, the collection, analysis and interpretation of data, the writing of the manuscript or the decision to submit the manuscript. Detailed acknowledgments for the dbGaP data sets are provided in the Supplementary Note.

Author information


  1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Virginia Perez-Andreu
    • , Wenjian Yang
    • , Heng Xu
    • , Shuyu E
    • , Joshua Yew-Suang Lim
    • , Colton Smith
    • , William E Evans
    • , Mary V Relling
    •  & Jun J Yang
  2. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Kathryn G Roberts
    •  & Charles G Mullighan
  3. Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.

    • Richard C Harvey
    • , I-Ming Chen
    •  & Cheryl L Willman
  4. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Cheng Cheng
    •  & Deqing Pei
  5. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

    • Julie Gastier-Foster
  6. Department of Pediatrics, Ohio State University School of Medicine, Columbus, Ohio, USA.

    • Julie Gastier-Foster
  7. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Joshua Yew-Suang Lim
  8. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yiping Fan
  9. Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, Florida, USA.

    • Meenakshi Devidas
  10. Johns Hopkins Medical Institute, Baltimore, Maryland, USA.

    • Michael J Borowitz
  11. Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Geoffrey Neale
  12. Department of Bioengineering & Therapeutic Science and Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Esteban G Burchard
    •  & Dara G Torgerson
  13. Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala.

    • Federico Antillon Klussmann
    •  & Cesar Rolando Najera Villagran
  14. Department of Pediatric Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Naomi J Winick
  15. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

    • Bruce M Camitta
  16. New York University Cancer Institute, New York, New York, USA.

    • Elizabeth Raetz
    •  & William L Carroll
  17. Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.

    • Brent Wood
  18. Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.

    • Feng Yue
  19. Maine Children's Cancer Program, Scarborough, Maine, USA.

    • Eric Larsen
  20. Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, Texas, USA.

    • W Paul Bowman
  21. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.

    • Mignon L Loh
  22. Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland, USA.

    • Michael Dean
  23. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Deepa Bhojwani
    •  & Ching-Hon Pui
  24. Department of Hematology and Oncology, Children's Hospital Colorado, University of Colorado, Aurora, Colorado, USA.

    • Stephen P Hunger


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J.J.Y. supervised the research. V.P.-A., S.P.H., C.L.W., C.G.M. and J.J.Y. conceived and designed the experiments. V.P.-A., K.G.R., R.C.H., J.G.-F., S.E., I.-M.C., G.N., E.G.B., D.G.T. and C.R.N.V. performed the experiments. V.P.-A., J.J.Y., R.C.H., W.Y., C.C., D.P., Y.F., M. Devidas, C.S. and G.N. performed statistical analysis. V.P.-A., K.G.R., R.C.H., W.Y., H.X., S.E., J.Y.-S.L., I.-M.C., Y.F., M.J.B., C.S., G.N., E.G.B., D.G.T., F.A.K., C.R.N.V., M.L.L., M. Devidas, D.B., C.-H.P., W.E.E., M.V.R., S.P.H., C.L.W. and C.G.M. analyzed the data. R.C.H., J.G.-F., J.Y.-S.L., Y.F., E.G.B., F.A.K., C.R.N.V., N.J.W., B.M.C., E.R., B.W., F.Y., W.L.C., E.L., W.P.B., M.L.L., M. Dean, S.P.H., C.L.W. and C.G.M. contributed reagents, materials and/or analysis tools. V.P.-A. and J.J.Y. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jun J Yang.

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