Somatic mutations precede acute myeloid leukemia years before diagnosis

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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Fig. 1: Spectrum of mutations seen at baseline years prior to the diagnosis of AML alongside matched controls.
Fig. 2: Multivariable analysis of the risk to develop AML associated with the presence of mutated genes.
Fig. 3: Time to AML diagnosis is influenced by mutation status.
Fig. 4: Mutations pose AML risk irrespective of the variant allele fraction.
Fig. 5: Clonal evolution towards AML in selected patients.

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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.).

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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.

Corresponding authors

Correspondence to Pinkal Desai or Duane C. Hassane.

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Supplementary information

Supplementary Text and Figures

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

Reporting Summary

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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Desai, P., Mencia-Trinchant, N., Savenkov, O. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24, 1015–1023 (2018). https://doi.org/10.1038/s41591-018-0081-z

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