The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,457
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
Self-citationdbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · cited 1×
“(15) not recoverable after thaw (3) unavailable (9)”
BackgroundAge-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531
Self-citationHigh-throughput droplet digital PCR system for absolute quantitation of DNA copy number
Hindson, B. J., Ness, K. D., Masquelier, D. A., Belgrader, P., Heredia, N. J., Makarewicz, A. J., Bright, I. J., Lucero, M. Y., Hiddessen, A. L., Legler, T. C., et al. (2011) · Analytical Chemistry · doi:10.1021/ac202028g · Cited by 2,792
Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations
Cho, Y., Gorina, S., Jeffrey, P. D., & Pavletich, N. P. (1994) · Science · doi:10.1126/science.8023157 · Cited by 2,559
COSMIC: exploring the world's knowledge of somatic mutations in human cancer
Forbes, S. A., Beare, D. M., Gunasekaran, P., Leung, K., Bindal, N., Boutselakis, H., Ding, M., Bamford, S., Cole, C. G., Ward, S. A., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1075 · Cited by 2,294
A unique chromatin signature uncovers early developmental enhancers in humans
Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J. (2011) · Nature · doi:10.1038/nature09692 · Cited by 2,233
Prescribing Personalized Nutrition for Cardiovascular Health: Are We Ready?
Juma, S., Imrhan, V., Vijayagopal, P., & Prasad, C. (2014) · Lifestyle Genomics · doi:10.1159/000370213 · Cited by 1,908
The complete genome of an individual by massively parallel DNA sequencing
Wheeler, D. A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., He, W., Chen, Y.-J., Makhijani, V., Roth, G. T., et al. (2008) · Nature · doi:10.1038/nature06884 · Cited by 1,838
Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S. F. A., Hakonarson, H., & Bucan, M. (2007) · Genome Research · doi:10.1101/gr.6861907 · Cited by 1,792
Chemically defined conditions for human iPSC derivation and culture
Chen, G., Gulbranson, D. R., Hou, Z., Bolin, J. M., Ruotti, V., Probasco, M. D., Smuga-Otto, K., Howden, S. E., Diol, N. R., Propson, N. E., et al. (2011) · Nature Methods · doi:10.1038/nmeth.1593 · Cited by 1,447
Somatic mutation in cancer and normal cells
Martincorena, I., & Campbell, P. J. (2015) · Science · doi:10.1126/science.aab4082 · Cited by 1,396
Schwartz, S. D., Regillo, C. D., Lam, B. L., Eliott, D., Rosenfeld, P. J., Gregori, N. Z., Hubschman, J.-P., Davis, J. L., Heilwell, G., Spirn, M., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61376-3 · Cited by 1,327
BigWig and BigBed: enabling browsing of large distributed datasets
Kent, W. J., Zweig, A. S., Barber, G. P., Hinrichs, A. S., & Karolchik, D. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq351 · Cited by 1,268
Derivation of human embryonic stem cells in defined conditions
Ludwig, T. E., Levenstein, M. E., Jones, J. M., Berggren, W. T., Mitchen, E. R., Frane, J. L., Crandall, L. J., Daigh, C. A., Conard, K. R., Piekarczyk, M. S., et al. (2006) · Nature Biotechnology · doi:10.1038/nbt1177 · Cited by 1,114
Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
Initiative, T. I. S. C. (2007) · Nature Biotechnology · doi:10.1038/nbt1318 · Cited by 1,078
A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
Marión, R. M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., & Blasco, M. A. (2009) · Nature · doi:10.1038/nature08287 · Cited by 1,028
Laurent, L. C., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J. V., Lee, S., Barrero, M. J., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.003 · Cited by 890
Bouaoun, L., Sonkin, D., Ardin, M., Hollstein, M., Byrnes, G., Zavadil, J., & Olivier, M. (2016) · Human Mutation · doi:10.1002/humu.23035 · Cited by 730
International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data
Zhang, J., Baran, J., Cros, A., Guberman, J. M., Haider, S. A., Hsu, J. C., Liang, Y., Rivkin, E., Wang, J., Whitty, B. R., et al. (2011) · Database · doi:10.1093/database/bar026 · Cited by 652
5-Methylcytosine as an Endogenous Mutagen in the Human LDL Receptor and p53 Genes
Rideout, W. M., Coetzee, G. A., Olumi, A. F., & Jones, P. A. (1990) · Science · doi:10.1126/science.1697983 · Cited by 640
Initiative, T. I. S. C. (2011) · Nature Biotechnology · doi:10.1038/nbt.2051 · Cited by 580
Malkin, D. M. (2011) · Genes & Cancer · doi:10.1177/1947601911413466 · Cited by 529
Jun, G., Flickinger, M., Hetrick, K. N., Romm, J. M., Doheny, K. F., Abecasis, G. R., Boehnke, M., & Kang, H. M. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.09.004 · Cited by 484
Two Supporting Factors Greatly Improve the Efficiency of Human iPSC Generation
Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.10.002 · Cited by 468
Willis, A. C., Jung, E. J., Wakefield, T., & Chen, X. (2004) · Oncogene · doi:10.1038/sj.onc.1207396 · Cited by 342
Good manufacturing practice and clinical-grade human embryonic stem cell lines
Unger, C. A., Skottman, H., Blomberg, P., Dilber, M. S., & Hovatta, O. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn079 · Cited by 255
Xie, R., Everett, L. J., Lim, H., Patel, N. A., Schug, J., KROON, E. J., Kelly, O., Wang, A., D’Amour, K. A., Robins, A. J., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.11.023 · Cited by 245
RIKEN suspends first clinical trial involving induced pluripotent stem cells
Garber, K. (2015) · Nature Biotechnology · doi:10.1038/nbt0915-890 · Cited by 215
Avery, S., Hirst, A. J., Baker, D., Lim, C. Y., Alagaratnam, S., Skotheim, R. I., Lothe, R. A., Pera, M. F., Colman, A., Robson, P., et al. (2013) · Stem Cell Reports · doi:10.1016/j.stemcr.2013.10.005 · Cited by 161
Merkle, F. T., Neuhausser, W. M., Santos, D., Valen, E., Gagnon, J. A., Maas, K., Sandoe, J., Schier, A. F., & Eggan, K. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.007 · Cited by 152
Self-citationDetecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells
Baker, D., Hirst, A. J., Gokhale, P. J., Juárez, M. A., Williams, S., Wheeler, M., Bean, K., Allison, T. F., Moore, H. D. M., Andrews, P. W., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.10.003 · Cited by 149
Nguyen, H. T., Geens, M., Mertzanidou, A., Jacobs, K., Heirman, C., Breckpot, K., & Spits, C. (2013) · Molecular Human Reproduction · doi:10.1093/molehr/gat077 · Cited by 111
Ganna, A., Genovese, G., Howrigan, D. P., Byrnes, A., Kurki, M., Zekavat, S. M., Whelan, C. W., Kals, M., Nivard, M. G., Bloemendal, A., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4404 · Cited by 89
Self-citationHuman Intestinal Tissue with Adult Stem Cell Properties Derived from Pluripotent Stem Cells
Forster, R. E., Chiba, K., Schaeffer, L., Regalado, S. G., Lai, C. S., Gao, Q., Kiani, S., Farin, H. F., Clevers, H. C., Cost, G. J., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.05.001 · Cited by 88
Heterogeneity of Li-Fraumeni Syndrome links to unequal gain-of-function effects of p53 mutations
Xu, J., Qian, J., Hu, Y., Wang, J., Zhou, X., Chen, H., & Fang, J. (2014) · Scientific Reports · doi:10.1038/srep04223 · Cited by 76
Amir, H., Touboul, T., Sabatini, K., Chhabra, D., Garitaonandia, I., Loring, J. F., Morey, R. E., & Laurent, L. C. (2016) · Stem Cells · doi:10.1002/stem.2550 · Cited by 39
Amir, H., Sabatini, K., Chhabra, D., Morey, R. E., & Laurent, L. C. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.07.1033 · Cited by 6
Culturing human pluripotent stem cells from diverse culture histories
Carver, A., Merkle, F. T., & Eggan, K. C. (2017) · Protocol Exchange · doi:10.1038/protex.2017.087 · Cited by 1
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906
Pluripotent Stem Cell-Based Cell Therapy—Promise and Challenges
Yamanaka, S. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.014 · Cited by 1,268
p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells
Ihry, R. J., Worringer, K. A., Salick, M. R., Frias, E., Ho, D., Theriault, K., Kommineni, S., Chen, J., Sondey, M., Ye, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0050-6 · Cited by 978
Transcription factor-mediated differentiation of human iPSCs into neurons
Fernandopulle, M. S., Prestil, R., Grunseich, C., Wang, C., Gan, L., & Ward, M. E. (2018) · Current Protocols in Cell Biology · doi:10.1002/cpcb.51 · Cited by 461
Understanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 538
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
