Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution
Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution
ABSTRACT Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation in these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients. DNMT3A mutations, which are associated with age-related clonal haematopoiesis, were also acquired in utero or childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency between JAK2V617F acquisition and clinical presentation was 31 years (range 12-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth and evolution drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.
Nangalia Jyoti、Lee Joe、Menzies Andrew、Godfrey Anna L、Campbell Peter J、Moore Luiza、Baxter E Joanna、Dawson Kevin J、Williams Nicholas、Green Anthony R、Hewinson James
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus||Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre||Department of Haematology, University of Cambridge||Department of Haematology, Cambridge University Hospitals NHS Foundation TrustWellcome Trust Sanger Institute, Wellcome Trust Genome Campus||Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical CentreWellcome Trust Sanger Institute, Wellcome Trust Genome CampusDepartment of Haematology, Cambridge University Hospitals NHS Foundation TrustWellcome Trust Sanger Institute, Wellcome Trust Genome Campus||Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre||Department of Haematology, University of CambridgeWellcome Trust Sanger Institute, Wellcome Trust Genome CampusDepartment of Haematology, University of CambridgeWellcome Trust Sanger Institute, Wellcome Trust Genome CampusWellcome Trust Sanger Institute, Wellcome Trust Genome CampusWellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre||Department of Haematology, University of Cambridge||Department of Haematology, Cambridge University Hospitals NHS Foundation TrustWellcome Trust Sanger Institute, Wellcome Trust Genome Campus
肿瘤学基础医学医学研究方法
Nangalia Jyoti,Lee Joe,Menzies Andrew,Godfrey Anna L,Campbell Peter J,Moore Luiza,Baxter E Joanna,Dawson Kevin J,Williams Nicholas,Green Anthony R,Hewinson James.Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution[EB/OL].(2025-03-28)[2025-06-23].https://www.biorxiv.org/content/10.1101/2020.11.09.374710.点此复制
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