Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Somatic mutations precede acute myeloid leukemia years before diagnosis


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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control. Clin. Trials 19, 61–109 (1998).

    Article  Google Scholar 

  9. Anderson, G. L. et al. Implementation of the Women’s Health Initiative study design. Ann. Epidemiol. 13, S5–S17 (2003).

    Article  PubMed  Google Scholar 

  10. Bergstralh, E. J., Kosanke, J. L.. & Jacobsen, S. J. Software for optimal matching in observational studies. Epidemiology 7, 331–332 (1996).

    PubMed  CAS  Google Scholar 

  11. Bowman, R. L., Busque, L. & Levine, R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22, 157–170 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Makishima, H. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119, 3203–3210 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Zhang, S. J. et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 119, 4480–4485 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kadia, T. M. et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer 15, 3484–3491 (2016).

    Article  CAS  Google Scholar 

  17. Samuelsen, S. O. A psudolikelihood approach to analysis of nested case–control studies. Biometrika 84, 379–394 (1997).

    Article  Google Scholar 

  18. Palmisano, M. et al. NPM1 mutations are more stable than FLT3 mutations during the course of disease in patients with acute myeloid leukemia. Haematologica 92, 1268–1269 (2007).

    Article  PubMed  Google Scholar 

  19. Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kim, S. S. et al. Loss-of-function mutations in the splicing factor ZRSR2 are common in blastic plasmacytoid dendritic cell neoplasm and have male predominance. Blood 122, 741 (2013).

    Google Scholar 

  22. Mori, T. et al. Somatic PHF6 mutations in1760 cases with various myeloid neoplasms. Leukemia 30, 2270–2273 (2016).

    Article  PubMed  CAS  Google Scholar 

  23. Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. The Cancer Genome Atlas Research Network.. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Article  PubMed Central  CAS  Google Scholar 

  25. Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209–2221 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Enasidenib approved for AML, but best uses unclear. Cancer Discov. 7, OF4 (2017).

  27. Lee, S. C. & Abdel-Wahab, O. Therapeutic targeting of splicing in cancer. Nat. Med. 22, 976–986 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Montalban-Bravo, G., Garcia-Manero, G. & Jabbour, E. Therapeutic choices after hypomethylating agent resistance for myelodysplastic syndromes. Curr. Opin. Hematol. 25, 146–153 (2018).

    PubMed  CAS  Google Scholar 

  29. Sabapathy, K. & Lane, D. P. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat. Rev. Clin. Oncol. 15, 13–30 (2018).

    Article  PubMed  CAS  Google Scholar 

  30. Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kircher, M., Sawyer, S. & Meyer, M. Double indexing overcomes inaccuracies in multiplex sequencing on the Illumina platform. Nucleic Acids Res. 40, e3 (2012).

    Article  PubMed  CAS  Google Scholar 

  32. Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at (2013).

  33. Lai, Z. et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 44, e108 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Li, H. Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 30, 2843–2851 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references


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 We are additionally grateful for funding from the Sandra and Edward Meyer Cancer Center, which partially supported this study (D.C.H.).

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declares no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Desai, P., Mencia-Trinchant, N., Savenkov, O. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 24, 1015–1023 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing