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; Alan J Warren

doi:10.1038/s41467-023-40896-5

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^*Alan J Warren^*

^*Corresponding author for this work

Department of Clinical Immunology

4 Citations (Scopus)

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.

Original language	English
Article number	5092
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	5092
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-023-40896-5
Publication status	Published - 22 Aug 2023

Keywords

Humans
Young Adult
Adult
Germ Cells
Chromosomes, Human, Pair 7
Gene Dosage
Hematopoietic Stem Cells
Mutation

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Machado, H. E., Øbro, N. F., Williams, N., Tan, S., Boukerrou, A. Z., Davies, M., Belmonte, M., Mitchell, E., Baxter, E. J., Mende, N., Clay, A., Ancliff, P., Köglmeier, J., Killick, S. B., Kulasekararaj, A., Meyer, S., Laurenti, E., Campbell, P. J., Kent, D. G., ... Warren, A. J. (2023). Convergent somatic evolution commences in utero in a germline ribosomopathy. Nature Communications, 14(1), 5092. Article 5092. https://doi.org/10.1038/s41467-023-40896-5

Machado, HE, Øbro, NF, Williams, N, Tan, S, Boukerrou, AZ, Davies, M, Belmonte, M, Mitchell, E, Baxter, EJ, Mende, N, Clay, A, Ancliff, P, Köglmeier, J, Killick, SB, Kulasekararaj, A, Meyer, S, Laurenti, E, Campbell, PJ, Kent, DG, Nangalia, J & Warren, AJ 2023, 'Convergent somatic evolution commences in utero in a germline ribosomopathy', Nature Communications, vol. 14, no. 1, 5092, pp. 5092. https://doi.org/10.1038/s41467-023-40896-5

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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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Convergent somatic evolution commences in utero in a germline ribosomopathy

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Keywords

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