Projectdetails

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Somatic mutations in peripheral blood of healthy individuals (clonal hematopoiesis); clinical implications and relation to ageing manifestations of the hematopoietic system

Keywords:
leukemia hematopoiesis mutations

Researchers:
dr. G.A. Huls
I.A. van Zeventer

Nature of the research:
Clinical/translational research. The student will work with large datasets and targeted next-generation sequencing data to detect somatic mutations in peripheral blood.

Fields of study:
haematology genetics

Background / introduction
It is likely that hematopoietic cancer arises from the combined effect of multiple somatic mutations, eventually leading to clonal expansion and proliferation of malignant cells. There is now increasing evidence that somatic mutations in peripheral blood cells are detected in (healthy) ageing individuals, referred to as clonal hematopoiesis. When carrying clonal hematopoiesis, these individuals have a higher risk for development of a myelodysplastic syndrome or acute myeloid leukemia. However, the clinical implications of clonal hematopoiesis are still largely unclear. Should we introduce population-based screening? Research is ongoing to distinguish pre-leukemia from “random” genetic hits as a result of ageing.
Research question / problem definition
- Study the clinical implications of clonal hematopoiesis in healthy individuals
- Study the relation between clonal hematopoiesis and ageing manifestations of the hematopoietic system, including peripheral cytopenias
Workplan
You will work on your own research project(s) and participate in all aspects of the research, including study design, performing analyses and reporting results. Most of the projects are carried out within the prospective Lifelines cohort, meaning that no retrospective data collection is involved. There is daily support available for help with programming/statistical analyses. There are numerous possibilities for extension of the research into a MD/PhD trajectory.
References
1. Gondek LP, DeZern AE. Assessing clonal haematopoiesis: clinical burdens and benefits of diagnosing myelodysplastic syndrome precursor states. Lancet Haematol. 2020 Jan;7(1):e73-e81. https://doi.org/10.1016/S2352-3026(19)30211-X
2. Shlush LI. Age-related clonal hematopoiesis. Blood 2018;131(5):496–504. https://doi.org/10.1182/blood-2017-07-746453
3. Jaiswal S et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine 2014;371(26):2488-2498.
4. Genovese G et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. New England Journal of Medicine 2014;371(26):2477-2487.
5. Desai P et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med. 2018;24(7):1015-1023.
6. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16.
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