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dc.contributor.authorWilliams, Nicholas
dc.contributor.authorLee, Joe
dc.contributor.authorMitchell, Emily
dc.contributor.authorMoore, Luiza
dc.contributor.authorBaxter, E Joanna
dc.contributor.authorHewinson, James
dc.contributor.authorDawson, Kevin J
dc.contributor.authorMenzies, Andrew
dc.contributor.authorGodfrey, Anna L
dc.contributor.authorGreen, Anthony R
dc.contributor.authorCampbell, Peter J
dc.contributor.authorNangalia, Jyoti
dc.date.accessioned2022-01-22T00:31:32Z
dc.date.available2022-01-22T00:31:32Z
dc.date.issued2022-02
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332879
dc.description.abstractMutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. 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. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F 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 JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F 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.
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleLife histories of myeloproliferative neoplasms inferred from phylogenies.
dc.typeArticle
dc.publisher.departmentWellcome Trust - Medical Research Council Cambridge Stem Cell Institute
dc.date.updated2022-01-21T10:51:50Z
prism.publicationNameNature
dc.identifier.doi10.17863/CAM.80309
dcterms.dateAccepted2021-12-06
rioxxterms.versionofrecord10.1038/s41586-021-04312-6
rioxxterms.versionAM
dc.contributor.orcidWilliams, Nicholas [0000-0003-3989-9167]
dc.contributor.orcidMoore, Luiza [0000-0001-5315-516X]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
dc.contributor.orcidNangalia, Jyoti [0000-0001-7122-4608]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_PC_17230)
pubs.funder-project-idWellcome Trust (104710/Z/14/Z)
cam.issuedOnline2022-01-20
cam.orpheus.success2022-01-21 - Embargo set during processing via Fast-track
cam.depositDate2022-01-21
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2022-07-20


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