AI Article Synopsis

  • Researchers studied clonal dynamics in individuals with Shwachman-Diamond syndrome by analyzing genetic mutations in blood-forming cells, revealing patterns of mutation and expansion.
  • They found that about 30% of the blood cell colonies had unique mutations, especially in genes related to cancer, which originated before birth and led to significant clonal growth.
  • The study indicates that while these mutations may help counteract the effects of a genetic disorder, they also increase the risk of cancer development linked to mutations in the TP53 gene.

Article Abstract

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10444798PMC
http://dx.doi.org/10.1038/s41467-023-40896-5DOI Listing

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