Bibliographic Details
| Title: |
Convergent somatic evolution commences in utero in a germline ribosomopathy. |
| Authors: |
Machado, Heather E., Øbro, Nina F., Williams, Nicholas, Tan, Shengjiang, Boukerrou, Ahmed Z., Davies, Megan, Belmonte, Miriam, Mitchell, Emily, Baxter, E. Joanna, Mende, Nicole, Clay, Anna, Ancliff, Philip, Köglmeier, Jutta, Killick, Sally B., Kulasekararaj, Austin, Meyer, Stefan, Laurenti, Elisa, Campbell, Peter J., Kent, David G., Nangalia, Jyoti |
| Source: |
Nature Communications; 8/22/2023, Vol. 14 Issue 1, p1-14, 14p |
| Subject Terms: |
CONVERGENT evolution, SOMATIC mutation, HEMATOPOIETIC stem cells, WHOLE genome sequencing, GERM cells |
| 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. Shwachman-Diamond Syndrome (SDS) is an inherited ribosome assembly disorder that increases the risk for haematopoietic malignancies. Here, the authors analysed clonal selection and evolution in SDS by sequencing patient-derived haematopoietic stem/progenitor cell colonies and exploring the function of key drivers in model organisms. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
