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Acute myeloid leukemia

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia

Leukemia volume 31, pages 1325–1332 (2017)Cite this article

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Abstract

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children’s Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10−4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10−5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

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Acknowledgements

The work was supported by the National Institutes of Health (grant numbers GM 92666, GM 115279, CA142665, CA 21765, CA 176063, CA 36401, CA 156449, CA98543 and CA 180886 (COG Chair's grant), CA98413 and CA180899 (COG Statistical Center), CA114766 (COG Specimen Banking), U01-HG04603, RC2- GM092618, R01-LM010685, 5T32-GM007569); Leukemia Lymphoma Society (grant number 6168); and by the American Lebanese Syrian Associated Charities. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author contributions

MVR and JJY contributed to the conception and design of the study. EL, LBR, CAF, JRM, SWP, RJA, ELL, BD, SJ, C-HP, EAR, NJW, WLC, SPH, MLL, MD, WEE, JJY and MVR contributed to the provision of study materials, patient recruitment, or acquisition of data. SEK, CC, XC and MVR contributed to data analysis and interpretation. All authors contributed to the drafting and reviewing of the manuscript and gave their final approval to submit for publication.

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Authors and Affiliations

  1. Comprehensive Cancer Center, St Jude Children’s Research Hospital, Memphis, TN, USA

    S E Karol

  2. Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA

    S E Karol, S Jeha & C-H Pui

  3. Department of Pediatrics, Maine Medical Center, Portland, ME, USA

    E Larsen

  4. Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, TN, USA

    C Cheng & X Cao

  5. Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA

    W Yang, J R McCorkle, S W Paugh, R J Autry, E Lopez-Lopez, B Diouf, W E Evans, J J Yang & M V Relling

  6. Department of Pharmacy Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    L B Ramsey

  7. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    C A Fernandez

  8. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    E A Raetz

  9. Department of Pediatrics, University of Texas, Southwestern Medical Center, Dallas, TX, USA

    N J Winick

  10. Department of Pediatrics and Pathology, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA

    W L Carroll

  11. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    S P Hunger

  12. Department of Pediatrics, University of California School of Medicine, San Francisco, CA, USA

    M L Loh

  13. Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL, USA

    M Devidas

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  1. S E Karol
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  2. E Larsen
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  3. C Cheng
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  4. X Cao
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Correspondence to M V Relling.

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Karol, S., Larsen, E., Cheng, C. et al. Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia. Leukemia 31, 1325–1332 (2017). https://doi.org/10.1038/leu.2017.24

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