Convergent somatic evolution commences in utero in a germline ribosomopathy.

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Machado, Heather E 
Øbro, Nina F 
Tan, Shengjiang 
Boukerrou, Ahmed Z 

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.


Acknowledgements: J.N. is supported by a Cancer Research UK Fellowship and work in the J.N. lab is supported by the Wellcome Trust, Cancer Research UK, Alborada Trust, Rosetrees Trust and the MPN Research Foundation. Work in the D.G.K. laboratory is supported by a European Research Council Starting Grant (ERC-2016-STG-715371), the Bill and Melinda Gates Foundation (INV-002189 and INV-038816) and a Cancer Research UK Programme Foundation Award (DCRPGF\100008). A.J.W. was supported by a Blood Cancer UK Programme Continuity Grant (21002 to A.J.W.), the UK Medical Research Council (MR/T012412/1), the Kay Kendall Leukaemia Fund, Rosetrees Trust, the SDS Foundation, the Shwachman-Diamond Project, the Butterfly Guild, SDS UK, the Connor Wright Project, the Cambridge National Institute for Health Research Biomedical Research Centre and the European Cooperation in Science and Technology (COST) Action CA18233 “European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet INNOCHRON” and CA21154, “Translational control in Cancer European Network, TRANSLACORE”. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust-MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. The authors would also like to thank the individuals for donating the samples that have been used in this study.

Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi:; Grant(s): ERC-2016-STG-715371

Humans, Young Adult, Adult, Germ Cells, Chromosomes, Human, Pair 7, Gene Dosage, Hematopoietic Stem Cells, Mutation
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Nat Commun
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Shwachman-Diamond Syndrome Foundation (SDSF/SDP/2021)
European Research Council (715371)
MRC (MR/T012412/1)
Blood Cancer UK (21002)