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Prediction of acute myeloid leukaemia risk in healthy individuals

Author

Listed:
  • Sagi Abelson

    (Princess Margaret Cancer Centre, University Health Network (UHN))

  • Grace Collord

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge)

  • Stanley W. K. Ng

    (Institute of Biomaterials and Biomedical Engineering, University of Toronto)

  • Omer Weissbrod

    (Weizmann Institute of Science)

  • Netta Mendelson Cohen

    (Weizmann Institute of Science)

  • Elisabeth Niemeyer

    (Weizmann Institute of Science)

  • Noam Barda

    (Clalit Research Institute)

  • Philip C. Zuzarte

    (Ontario Institute for Cancer Research)

  • Lawrence Heisler

    (Ontario Institute for Cancer Research)

  • Yogi Sundaravadanam

    (Ontario Institute for Cancer Research)

  • Robert Luben

    (University of Cambridge School of Clinical Medicine)

  • Shabina Hayat

    (University of Cambridge School of Clinical Medicine)

  • Ting Ting Wang

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    University of Toronto)

  • Zhen Zhao

    (Princess Margaret Cancer Centre, University Health Network (UHN))

  • Iulia Cirlan

    (Princess Margaret Cancer Centre, University Health Network (UHN))

  • Trevor J. Pugh

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    Ontario Institute for Cancer Research
    University of Toronto)

  • David Soave

    (Ontario Institute for Cancer Research)

  • Karen Ng

    (Ontario Institute for Cancer Research)

  • Calli Latimer

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Claire Hardy

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Keiran Raine

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • David Jones

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Diana Hoult

    (MRC Epidemiology Unit, University of Cambridge)

  • Abigail Britten

    (MRC Epidemiology Unit, University of Cambridge)

  • John D. McPherson

    (Ontario Institute for Cancer Research)

  • Mattias Johansson

    (International Agency for Research on Cancer, World Health Organization)

  • Faridah Mbabaali

    (Ontario Institute for Cancer Research)

  • Jenna Eagles

    (Ontario Institute for Cancer Research)

  • Jessica K. Miller

    (Ontario Institute for Cancer Research)

  • Danielle Pasternack

    (Ontario Institute for Cancer Research)

  • Lee Timms

    (Ontario Institute for Cancer Research)

  • Paul Krzyzanowski

    (Ontario Institute for Cancer Research)

  • Philip Awadalla

    (Ontario Institute for Cancer Research)

  • Rui Costa

    (European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus)

  • Eran Segal

    (Weizmann Institute of Science)

  • Scott V. Bratman

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    Ontario Institute for Cancer Research
    University of Toronto)

  • Philip Beer

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Sam Behjati

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge)

  • Inigo Martincorena

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Jean C. Y. Wang

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    University of Toronto
    University Health Network)

  • Kristian M. Bowles

    (The University of East Anglia
    Norfolk and Norwich University Hospitals NHS Trust)

  • J. Ramón Quirós

    (Public Health Directorate)

  • Anna Karakatsani

    (Hellenic Health Foundation
    2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Haidari)

  • Carlo Vecchia

    (Hellenic Health Foundation
    Università degli Studi di Milano)

  • Antonia Trichopoulou

    (Hellenic Health Foundation)

  • Elena Salamanca-Fernández

    (Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada
    CIBER Epidemiology and Public Health CIBERESP)

  • José M. Huerta

    (CIBER Epidemiology and Public Health CIBERESP
    Murcia Regional Health Council, IMIB-Arrixaca)

  • Aurelio Barricarte

    (CIBER Epidemiology and Public Health CIBERESP
    Navarra Public Health Institute
    Navarra Institute for Health Research)

  • Ruth C. Travis

    (Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford)

  • Rosario Tumino

    (Cancer Registry and Histopathology Department, Civic-M. P. Arezzo Hospital, Azienda Sanitaria Provinciale)

  • Giovanna Masala

    (Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute – ISPO)

  • Heiner Boeing

    (German Institute of Human Nutrition (DIfE))

  • Salvatore Panico

    (Dipartimento Di Medicina Clinica E Chirurgia, Federico II University)

  • Rudolf Kaaks

    (German Cancer Research Center (DKFZ))

  • Alwin Krämer

    (Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg)

  • Sabina Sieri

    (Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Elio Riboli

    (School of Public Health, Imperial College London)

  • Paolo Vineis

    (School of Public Health, Imperial College London)

  • Matthieu Foll

    (International Agency for Research on Cancer, World Health Organization)

  • James McKay

    (International Agency for Research on Cancer, World Health Organization)

  • Silvia Polidoro

    (Italian Institute for Genomic Medicine)

  • Núria Sala

    (Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory, Catalan Institute of Oncology, ICO-IDIBELL)

  • Kay-Tee Khaw

    (University of Cambridge)

  • Roel Vermeulen

    (Division of Environmental Epidemiology and Veterinary Public Health, Institute for Risk Assessment Sciences, Utrecht University)

  • Peter J. Campbell

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge)

  • Elli Papaemmanuil

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    Center for Molecular Oncology and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center)

  • Mark D. Minden

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    University of Toronto
    University of Toronto
    University Health Network)

  • Amos Tanay

    (Weizmann Institute of Science)

  • Ran D. Balicer

    (Clalit Research Institute)

  • Nicholas J. Wareham

    (MRC Epidemiology Unit, University of Cambridge)

  • Moritz Gerstung

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI, Wellcome Genome Campus)

  • John E. Dick

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    University of Toronto)

  • Paul Brennan

    (International Agency for Research on Cancer, World Health Organization)

  • George S. Vassiliou

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    University of Cambridge
    Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute, University of Cambridge)

  • Liran I. Shlush

    (Princess Margaret Cancer Centre, University Health Network (UHN)
    Weizmann Institute of Science
    Rambam Healthcare Campus)

Abstract

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4–8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Suggested Citation

  • Sagi Abelson & Grace Collord & Stanley W. K. Ng & Omer Weissbrod & Netta Mendelson Cohen & Elisabeth Niemeyer & Noam Barda & Philip C. Zuzarte & Lawrence Heisler & Yogi Sundaravadanam & Robert Luben &, 2018. "Prediction of acute myeloid leukaemia risk in healthy individuals," Nature, Nature, vol. 559(7714), pages 400-404, July.
    • Handle: RePEc:nat:nature:v:559:y:2018:i:7714:d:10.1038_s41586-018-0317-6
    DOI: 10.1038/s41586-018-0317-6
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    Citations

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    Cited by:

    1. Soave, David & Lawless, Jerald F., 2023. "Regularized regression for two phase failure time studies," Computational Statistics & Data Analysis, Elsevier, vol. 182(C).
    2. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Brooks A. Benard & Logan B. Leak & Armon Azizi & Daniel Thomas & Andrew J. Gentles & Ravindra Majeti, 2021. "Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. N. Zioni & A. Akhiad Bercovich & N. Chapal-Ilani & Tal Bacharach & N. Rappoport & A. Solomon & R. Avraham & E. Kopitman & Z. Porat & M. Sacma & G. Hartmut & M. Scheller & C. Muller-Tidow & D. Lipka & , 2023. "Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. José Guilherme Almeida & Emma Gudgin & Martin Besser & William G. Dunn & Jonathan Cooper & Torsten Haferlach & George S. Vassiliou & Moritz Gerstung, 2023. "Computational analysis of peripheral blood smears detects disease-associated cytomorphologies," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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