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Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

Florian Zink, Simon N. Stacey, Gudmundur L. Norddahl, Michael L. Frigge, Olafur T. Magnusson, Ingileif Jonsdottir, Thorgeir E. Thorgeirsson, Asgeir Sigurdsson, Sigurjon A. Gudjonsson, Julius Gudmundsson, Jon G. Jonasson, Laufey Tryggvadottir, Thorvaldur Jonsson, Agnar Helgason, Arnaldur Gylfason, Patrick Sulem, Thorunn Rafnar, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Gisli Masson, Augustine Kong and Kari Stefansson

Key points

  • Whole genome sequencing of 11,262 Icelanders reveals that clonal hematopoiesis is very common in the elderly.

  • Somatic mutation of some genes is strongly associated with clonal hematopoiesis, but in most cases no driver mutations were evident.

Abstract

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells are derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) genes are thought to be responsible for at least some cases of CH. Using whole genome sequencing of 11,262 Icelanders, we found 1,403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, irrespective of whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending towards inevitability. We show that somatic mutations in TET2, DNMT3A, ASXL1 and PPM1D are associated with CH at high significance. However known CD mutations were evident in only a fraction of CH cases. Nevertheless, the highly prevalent CH that we detect associates with increased mortality rates, risk of hematological malignancy, smoking behaviour, telomere length, Y-chromosome loss and other phenotypic characteristics. Modelling suggests that some CH cases could arise in the absence of CD mutations due to neutral drift acting on a small population of active hematopoietic stem cells. Finally, we find a germline deletion in intron 3 of the telomerase reverse transcriptase (TERT) gene that predisposes to CH (rs34002450, P=7.4x10-12, OR=1.37).

  • Submitted February 21, 2017.
  • Accepted May 1, 2017.