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Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis

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Abstract

Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.

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Figure 1: Somatic TET2 mutations are present in normal elderly individuals with myeloid skewing and are associated with epigenetic alterations.

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Acknowledgements

We thank members of the Levine and Busque laboratories for helpful comments and discussion. This work was supported by a grant from the National Cancer Institute Physical Sciences Oncology Center (U54CA143798-01) to R.L.L. and A.M., by grant 1R01CA138234-01 to R.L.L. and by grants 1R01CA129831 and 1R01CA129831-03S1 to L.A.G. from the National Cancer Institute. A. Vasanthakumar is supported by a US National Institutes of Health F32 award. M.E.F. is supported by a Leukemia and Lymphoma Society Special Fellow award and a Doris Duke Charitable Foundation Clinical Scientist Development Award. O.A.-W. is an American Society of Hematology Basic Research Fellow. A.M. is a Burroughs Wellcome Clinical Translational Scholar and is also supported by the Sackler Center for Biomedical and Physical Sciences. R.L.L. is an Early Career Award Recipient of the Howard Hughes Medical Institute. R.L.L. and A.M. are funded by Leukemia and Lymphoma Society Scholar Awards. All subjects answered a medical questionnaire and gave informed consent. The study was approved by the Maisonneuve-Rosemont Hospital's Ethics Committee in 1998 and is reapproved yearly in accordance with institutional bylaws.

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Author notes

  1. Lambert Busque and Jay P Patel: These authors contributed equally to this work.

  2. Omar Abdel-Wahab and Ross L Levine: These authors jointly directed this work.

Authors and Affiliations

  1. Research Centre, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada

    Lambert Busque & Luigina Mollica

  2. Department of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada

    Lambert Busque, Zineb Hamilou & Luigina Mollica

  3. University of Montreal, Montreal, Quebec, Canada

    Lambert Busque, Zineb Hamilou & Luigina Mollica

  4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Jay P Patel, Adriana Heguy, Parva K Bhatt, Cameron W Brennan, Omar Abdel-Wahab & Ross L Levine

  5. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Maria E Figueroa

  6. Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA

    Aparna Vasanthakumar & Lucy A Godley

  7. Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada

    Sylvie Provost

  8. Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Juan Li & Agnes Viale

  9. Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Maryam Hassimi & Nicholas Socci

  10. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Mithat Gonen

  11. Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York, USA

    Christopher E Mason

  12. Graduate School of Biomedical Sciences, Weill Medical College of Cornell University, New York, New York, USA

    Christopher E Mason, Ari Melnick & Ross L Levine

  13. Division of Hematology/Oncology, Weill Medical College of Cornell University, New York, New York, USA

    Ari Melnick

  14. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Cameron W Brennan

  15. Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Omar Abdel-Wahab & Ross L Levine

Authors
  1. Lambert Busque
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  2. Jay P Patel
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  3. Maria E Figueroa
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  4. Aparna Vasanthakumar
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  5. Sylvie Provost
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  6. Zineb Hamilou
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  7. Luigina Mollica
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  8. Juan Li
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  9. Agnes Viale
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  10. Adriana Heguy
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  11. Maryam Hassimi
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  12. Nicholas Socci
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  13. Parva K Bhatt
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  14. Mithat Gonen
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  15. Christopher E Mason
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  16. Ari Melnick
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  17. Lucy A Godley
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  18. Cameron W Brennan
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  19. Omar Abdel-Wahab
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  20. Ross L Levine
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Contributions

L.B., J.P.P., O.A.-W. and R.L.L. designed the study. L.B., S.P., Z.H. and L.M. collected samples and provided genetic and clinical annotation. J.P.P., J.L., A. Vasanthakumar, A.H., M.H., N.S., P.K.B., C.E.M. and C.W.B. performed sequence analysis and validated mutations. M.E.F., A. Viale, A.M. and L.A.G. performed methylation analysis. M.G. performed statistical analysis. L.B., J.P.P., O.A.-W. and R.L.L. wrote the manuscript.

Corresponding authors

Correspondence to Lambert Busque or Ross L Levine.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1 and 2 and Supplementary Tables 1–4 (PDF 1427 kb)

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Busque, L., Patel, J., Figueroa, M. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44, 1179–1181 (2012). https://doi.org/10.1038/ng.2413

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  • DOI: https://doi.org/10.1038/ng.2413

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