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Life histories of myeloproliferative neoplasms inferred from phylogenies
Open accessPublished version of a preprint
Abstract
Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited 1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2 V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2 V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2 V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2 V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.
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“Emerging evidence indicates somatic DNMT3A variants can be acquired early in life (12,13), before becoming almost ubiquitous in the aging population (14).”
From Txnip Enhances Fitness of Dnmt3a -Mutant Hematopoietic Stem Cells via p21 (2022) · cites this paper as [13]
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Metadata
- Authors
- Williams, N., Lee, J., Mitchell, E., Moore, L., Baxter, E. J., Hewinson, J., Dawson, K. J., Menzies, A., Godfrey, A. L., Green, A. R., Campbell, P. J., & Nangalia, J.
- Affiliations
- Wellcome Sanger Institute (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Nangalia, Jyoti
- Venue
- Nature
- Published
- 2022-01-20
- Volume
- 602
- Issue
- 7895
- Pages
- 162-168
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W4205211254
- Cited by
- 285
- References
- 64
- Citations by year
- 2026: 40 · 2025: 52 · 2024: 74 · 2023: 65 · 2022: 52
- FWCI
- 37.71
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- MPN Research Foundation
- Wellcome Trust (104710/Z/14/Z)
- Cancer Research UK (23917)
- Kay Kendall Leukaemia Fund
- Blood Cancer UK
- Medical Research Council (MC_PC_17230)
- Topics
- Health Sciences › Medicine › Hematology › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- myeloproliferative neoplasms, driver mutations, clonal evolution, JAK2 V617F mutation, DNMT3A, PPM1D, clonal expansion, mutation timing, carcinogenesis
- MeSH terms
- Protein Phosphatase 2C, Whole Genome Sequencing, Adult, Child, Preschool, Clone Cells, Humans, Mutation, Myeloproliferative Disorders, Neoplasms, Phylogeny, Janus Kinase 2
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