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Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
Open accessAbstract
Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.
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“and six specific variants in TP53 have been identified in several hPSC lines.165”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [165]
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“For pluripotent stem cells—embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)—there appears to be a selection advantage for mutations of some oncogenes, in particular for TP53 and BCOR, which can become fixed in culture74,75.”
From How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation (2018) · cites this paper as [74]
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Metadata
- Authors
- Merkle, F. T., Ghosh, S., Kamitaki, N., Mitchell, J., Avior, Y., Mello, C., Kashin, S., Mekhoubad, S., Ilic, D., Charlton, M., Saphier, G., Handsaker, R. E., Genovese, G., Bar, S., Benvenisty, N., McCarroll, S. A., & Eggan, K.
- Affiliations
- Broad Institute (US)
- Hebrew University of Jerusalem (IL)
- Harvard University (US)
- Corresponding author
- McCarroll, Steven A.
- Eggan, Kevin
- ORCID
- Venue
- Nature
- Published
- 2017-04-26
- Volume
- 545
- Issue
- 7653
- Pages
- 229-233
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5427175
- OpenAlex
- W2608500349
- Cited by
- 506
- References
- 44
- Citations by year
- 2026: 38 · 2025: 44 · 2024: 50 · 2023: 42 · 2022: 56 · 2021: 68 · 2020: 65 · 2019: 54 · 2018: 50 · 2017: 35
- FWCI
- 22.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust
- Academy of Medical Sciences (SBF001\1016)
- Rosetrees Trust (M108-F1)
- National Institutes of Health (5K99NS08371)
- Medical Research Council (MC_PC_12009, MR/P501967/1)
- National Heart, Lung, and Blood Institute (R01HL109525)
- National Human Genome Research Institute (R01HG006855)
- National Institute of General Medical Sciences (P01GM099117)
- National Institute of Neurological Disorders and Stroke (K99NS083713)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- human pluripotent stem cells, human embryonic stem cells, induced pluripotent stem cells, TP53 mutation, dominant-negative p53, somatic mosaicism, copy number variation, clonal expansion, tumour suppressor, DNA-binding domain, stem cell culture conditions, exome sequencing, RNA sequencing
- MeSH terms
- Human Embryonic Stem Cells, Protein Domains, Alleles, Cell Count, Cell Differentiation, Cell Division, Cell Line, DNA, DNA Mutational Analysis, Genes, Dominant, Humans, Mosaicism, Mutation, Neoplasms, Selection, Genetic, Genes, p53, Tumor Suppressor Protein p53, Loss of Heterozygosity, Induced Pluripotent Stem Cells, Exome
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