Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.
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Authors
Zink, FlorianStacey, Simon N
Norddahl, Gudmundur L
Frigge, Michael L
Magnusson, Olafur T
Jonsdottir, Ingileif
Thorgeirsson, Thorgeir E
Sigurdsson, Asgeir
Gudjonsson, Sigurjon A
Gudmundsson, Julius
Jonasson, Jon G
Tryggvadottir, Laufey
Jonsson, Thorvaldur
Helgason, Agnar
Gylfason, Arnaldur
Sulem, Patrick
Rafnar, Thorunn
Thorsteinsdottir, Unnur
Gudbjartsson, Daniel F
Masson, Gisli
Kong, Augustine
Stefansson, Kari
Issue Date
2017-08-10
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Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. 2017, 130 (6):742-752 BloodAbstract
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is 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 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward 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 we detect associates with increased mortality rates, risk for hematological malignancy, smoking behavior, telomere length, Y-chromosome loss, and other phenotypic characteristics. Modeling suggests some CH cases could arise in the absence of CD mutations as a result of 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 = 7.4 × 10(-12); odds ratio, 1.37).Additional Links
http://www.bloodjournal.org/content/130/6/742Rights
Archived with thanks to Bloodae974a485f413a2113503eed53cd6c53
10.1182/blood-2017-02-769869
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