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High prevalence of acquired cancer-related mutations in 146 human pluripotent stem cell lines and their differentiated derivatives

Nature Biotechnology (2024)Cite this article

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Abstract

To survey cancer-related mutations in human pluripotent stem cells and their derivatives, we analyzed >2,200 transcriptomes from 146 independent lines in the NCBI’s Sequence Read Archive. Twenty-two per cent of samples had at least one cancer-related mutation; of these, 64% had TP53 mutations, which conferred a pronounced selective advantage, perturbed target gene expression and altered cellular differentiation. These findings underscore the need for robust surveillance of cancer-related mutations in pluripotent cells, especially in clinical applications.

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Fig. 1: Distribution of mutations identified in hPS cell-derived samples from 178 differentiation studies.
Fig. 2: Functional importance of cancer-related TP53 mutations in undifferentiated and differentiated hPS cells.

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Data availability

All RNA-seq data are available in NCBI’s Sequence Read Archive referenced through accession codes provided in Supplementary Table 1.

Code availability

All code sections implemented for data processing and analysis are available at https://github.com/elyadlezmi/cancerMutAtDifferentiation.

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Acknowledgements

We thank all members of The Azrieli Center for Stem Cells and Genetic Research for critical reading of the manuscript. This manuscript is dedicated to the memory of the late O. Yanuka, manager of The Azrieli Center for Stem Cells and Genetic Research. N.B. was supported by the Azrieli Foundation, the Rosetrees Trust, the Israel Science Foundation (no. 2054/22), the ISF–Israel Precision Medicine Partnership Program (no. 3605/21) and the HEAL project, funded by the European Union, EU Horizon (no. 101056712). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or EU Horizon; neither the European Union nor EU Horizon can be held responsible for them. N.B. is the Herbert Cohn Chair in Cancer Research.

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Author notes

  1. These authors contributed equally: Elyad Lezmi, Jonathan Jung.

Authors and Affiliations

  1. Department of Genetics, The Azrieli Center for Stem Cells and Genetic Research, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel

    Elyad Lezmi, Jonathan Jung & Nissim Benvenisty

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  1. Elyad Lezmi
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  2. Jonathan Jung
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Contributions

E.L., J.J. and N.B. designed the research. J.J. gathered, verified and downloaded the data for analysis. E.L. updated the pipeline to fit large-scale datasets. E.L., J.J. and N.B. interpreted the results and prepared the manuscript. N.B. supervised the study and secured funding.

Corresponding author

Correspondence to Nissim Benvenisty.

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The authors declare no competing interests.

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Peer review information

Nature Biotechnology thanks Jane Lebkowski, Leendert Looijenga, Christine Wells and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2.

Reporting Summary

Supplementary Table 1

Dataset of all validated samples processed by the pipeline.

Supplementary Table 2

Dataset of all cancer-related mutations identified.

Supplementary Table 3

Dataset of mutations acquired during the differentiation process.

Supplementary Table 4

hPS cell layout of the three most common cell lines (WT or TP53 mutated).

Supplementary Table 5

Samples from different time points of neural differentiation (WT or TP53 mutated).

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Lezmi, E., Jung, J. & Benvenisty, N. High prevalence of acquired cancer-related mutations in 146 human pluripotent stem cell lines and their differentiated derivatives. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-023-02090-2

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