Convergent somatic evolution commences in utero in a germline ribosomopathy

Heather E. Machado, Nina F. Øbro, Nicholas Williams, Shengjiang Tan, Ahmed Z. Boukerrou, Megan Davies, Miriam Belmonte, Emily Mitchell, E. Joanna Baxter, Nicole Mende, Anna Clay, Philip Ancliff, Jutta Köglmeier, Sally B. Killick, Austin Kulasekararaj, Stefan Meyer, Elisa Laurenti, Peter J. Campbell, David G. Kent (), Jyoti Nangalia () and Alan J. Warren ()
Additional contact information
Heather E. Machado: Wellcome Genome Campus
Nina F. Øbro: University of Cambridge
Nicholas Williams: Wellcome Genome Campus
Shengjiang Tan: University of Cambridge
Ahmed Z. Boukerrou: University of Cambridge
Megan Davies: University of Cambridge
Miriam Belmonte: University of Cambridge
Emily Mitchell: Wellcome Genome Campus
E. Joanna Baxter: University of Cambridge
Nicole Mende: University of Cambridge
Anna Clay: University of Cambridge
Philip Ancliff: Great Ormond Street Hospital for Children NHS Foundation Trust
Jutta Köglmeier: Great Ormond Street Hospital for Children NHS Foundation Trust
Sally B. Killick: University Hospitals Dorset NHS Foundation Trust, The Royal Bournemouth Hospital
Austin Kulasekararaj: King’s College Hospital NHS Foundation Trust and King’s College London
Stefan Meyer: University of Manchester, Manchester Cancer Research Centre
Elisa Laurenti: University of Cambridge
Peter J. Campbell: Wellcome Genome Campus
David G. Kent: University of Cambridge
Jyoti Nangalia: Wellcome Genome Campus
Alan J. Warren: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40896-5

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