Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure.

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Tác giả: Alex Bick, Tamir Chandra, Simon Cox, Francesco Cucca, Ian J Deary, Edoardo Fiorillo, Sarah Harris, Michael Honigberg, Kristina Kirschner, E Gozde Kosebent, Eric Latorre-Crespo, Louise MacGillivray, Riccardo Marioni, Michele Marongiu, Lee Murphy, Valeria Orrù, Alexander P Reiner, Neil A Robertson, Linus Schumacher, Mesbah Uddin, Eric Whitsel

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : bioRxiv : the preprint server for biology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 723404

Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.
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