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Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis

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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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.

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Correspondence to Lambert Busque or Ross L Levine.

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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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