Life histories of myeloproliferative neoplasms inferred from phylogenies

Nicholas Williams, Joe Lee, Emily Mitchell, Luiza Moore, E. Joanna Baxter, James Hewinson, Kevin J. Dawson, Andrew Menzies, Anna L. Godfrey, Anthony R. Green, Peter J. Campbell and Jyoti Nangalia ()
Additional contact information
Nicholas Williams: Wellcome Genome Campus
Joe Lee: Wellcome Genome Campus
Emily Mitchell: Wellcome Genome Campus
Luiza Moore: Wellcome Genome Campus
E. Joanna Baxter: University of Cambridge
James Hewinson: Wellcome Genome Campus
Kevin J. Dawson: Wellcome Genome Campus
Andrew Menzies: Wellcome Genome Campus
Anna L. Godfrey: Cambridge University Hospitals NHS Foundation Trust
Anthony R. Green: Jeffrey Cheah Biomedical Centre
Peter J. Campbell: Wellcome Genome Campus
Jyoti Nangalia: Wellcome Genome Campus

Nature, 2022, vol. 602, issue 7895, 162-168

Abstract: Abstract Mutations 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.

Date: 2022
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DOI: 10.1038/s41586-021-04312-6

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