ESPEYB19 15. Editors’ Choice Basic Science and Genetics (5 abstracts)
15.18. Life histories of myeloproliferative neoplasms inferred from phylogenies
Williams N , Lee J , Mitchell E , Moore L , Baxter EJ , Hewinson J , Dawson KJ , Menzies A , Godfrey AL , Green AR , Campbell PJ & Nangalia J
Nature. 2022;602(7895):162-8. doi: 10.1038/s41586-021-04312-6.PubMed ID: 35058638
Brief summary: This study performed whole-genome sequencing (WGS) of 1013 clonal haematopoietic cell colonies from 12 adult patients aged 20–81 years with myeloproliferative neoplasms, a form of blood cancer. They identified 580 133 somatic mutations and used these to reconstruct haematopoietic clonal histories. Key somatic (i.e. non-germline) driver mutations were estimated to have occurred early in life, including fetal life and early childhood.
These remarkable findings extend the list of possible mechanisms linking environmental exposures during early life, including in utero development, to risks of diseases they are typically thought of as ageing processes. The mechanism highlighted here is the acquisition by cells of somatic mutations in their DNA sequence, which they show can happen many decades before the manifestation of disease.
One key driver mutation, JAK2V617F was estimated to have been acquired from 33 weeks gestation onwards. Another, DNMT3A mutations was acquired from 8 weeks of gestation onwards, and a PPM1D mutation was acquired by age 5.8 years. The duration between JAK2V617F acquisition and disease diagnosis was on average 30 years (range 11–54 years), during which time cells carrying these mutations proliferate extensively giving rise to distinct ‘clones of cells’, and the subsequent acquisition of additional driver mutations is separated by decades across life.
These findings identify a life-long pathogenesis of adult myeloproliferative neoplasms. Other types of age-related genomic events that lead to clonal expansions, such mosaic loss of chromosome Y, can have impacts on more diverse cancer and non-cancer diseases (1). Identification of the triggers for these somatic mutations and their detection may provide new avenues for early life disease prediction and prevention.
Reference: 1. Sano S, et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science 2022; 377(6603);292–297.
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ESPE Yearbook of Paediatric Endocrinology
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