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Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly
- Source :
- Blood. 130:742-752
- Publication Year :
- 2017
- Publisher :
- American Society of Hematology, 2017.
-
Abstract
- 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).
- Subjects :
- 0301 basic medicine
Genetics
Mutation
education.field_of_study
Lineage (genetic)
Hematopoiesis and Stem Cells
Somatic cell
Immunology
Population
Hematopoietic stem cell
Cell Biology
Hematology
Biology
medicine.disease_cause
Biochemistry
Germline
Telomere
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine
Telomerase reverse transcriptase
education
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....51393497c99fdbf83736ceabc42d9c57