Abstract

The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.

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Acknowledgements

We acknowledge all our donors to Leukemia Fighters, without whom this work would not have been possible; the women who generously participated in the WHI study. We thank J. Z. Xiang and the Weill Cornell Genomics Core Facility as well as J. Catalano of the Englander Institute for Precision Medicine for assistance in sequencing; L.-B. Yan for technical assistance. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221, and the Cancer Center Support Grant NIH:NCI P30CA022453. We acknowledge the dedicated efforts of investigators and staff at the WHI clinical centers, the WHI Clinical Coordinating Center, and the National Heart, Lung and Blood program office (listing available at http://www.whi.org). We are additionally grateful for funding from the Sandra and Edward Meyer Cancer Center, which partially supported this study (D.C.H.).

Author information

Author notes

  1. These authors contributed equally: Pinkal Desai, Nuria Mencia-Trinchant.

  2. These authors jointly supervised this work: Gail J. Roboz, Duane C. Hassane.

Affiliations

  1. Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA

    • Pinkal Desai
    • , Nuria Mencia-Trinchant
    • , Sangmin Lee
    • , Michael Samuel
    • , Ellen K. Ritchie
    • , Monica L. Guzman
    • , Gail J. Roboz
    •  & Duane C. Hassane
  2. Heath Care Policy and Research, Weill Cornell Medical College, New York, NY, USA

    • Oleksandr Savenkov
    •  & Karla V. Ballman
  3. Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    • Michael S. Simon
  4. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    • Gloria Cheang
  5. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA

    • Duane C. Hassane
  6. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA

    • Duane C. Hassane

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Contributions

P.D., M.S.S., M.L.G., G.J.R. and D.C.H. designed and supervised the study; P.D., N.M.-T., M.L.G., G.J.R. and D.C.H. wrote the manuscript; P.D. compiled epidemiological data; N.M.-T. performed experiments; P.D., N.M.-T., M.L.G. and D.C. H. analyzed data; P.D., N.M.-T., O.S., D.C.H. and K.V.B. performed and/or supervised statistical studies; G.C. performed experiments; S.L., M.S. and E.K.R. reviewed and interpreted data.

Competing interests

The authors declares no competing interests.

Corresponding authors

Correspondence to Pinkal Desai or Duane C. Hassane.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Methods, Supplementary Tables 1–5 and Supplementary Figures 1–23

  2. Reporting Summary

  3. Supplementary Dataset

    Somatic mutation calls; list of somatic mutations detected in this study. Includes data for all mutated participants and time points

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DOI

https://doi.org/10.1038/s41591-018-0081-z

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