Nature Genetics
37, 1099 - 1103 (2005)
Published online: 4 September 2005; | doi:10.1038/ng1631
Genomic alterations in cultured human embryonic stem cellsAnirban Maitra1, 2, 3, 12, Dan E Arking1, 12, Narayan Shivapurkar4, Morna Ikeda1, Victor Stastny4, Keyaunoosh Kassauei2, Guoping Sui2, David J Cutler1, Ying Liu5, Sandii N Brimble6, Karin Noaksson7, Johan Hyllner7, Thomas C Schulz6, Xianmin Zeng8, William J Freed8, Jeremy Crook9, Suman Abraham9, Alan Colman9, Peter Sartipy7, Sei-Ichi Matsui10, Melissa Carpenter11, Adi F Gazdar4, Mahendra Rao5
& Aravinda Chakravarti11
McKusick-Nathans Institute of Genetic Medicine, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, Maryland
21205, USA. 2
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, Maryland
21205, USA. 3
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, Maryland
21205, USA. 4
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 5
Laboratory of Neurosciences, National Institute on Aging, 333 Cassell Drive, Triad Bldg., Baltimore, Maryland
21224, USA. 6
BresaGen, Inc., Athens, Georgia, USA. 7
Cellartis AB, Goteborg, Sweden. 8
Cellular Neurobiology Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA. 9
ES Cell International, Singapore. 10
Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York, USA. 11
Robarts Research Institute, Ontario, Canada. 12
These authors contributed equally to this work.
Correspondence should be addressed to Aravinda Chakravarti aravinda@jhmi.edu or Mahendra Rao raomah@grc.nia.nih.gov Cultured human embryonic stem cell (hESC) lines are an invaluable resource because they provide a uniform and stable genetic system for functional analyses and therapeutic applications. Nevertheless, these dividing cells, like other cells, probably undergo spontaneous mutation at a rate of 10-9 per nucleotide. Because each mutant has only a few progeny, the overall biological properties of the cell culture are not altered unless a mutation provides a survival or growth advantage. Clonal evolution that leads to emergence of a dominant mutant genotype may potentially affect cellular phenotype as well. We assessed the genomic fidelity of paired early- and late-passage hESC lines in the course of tissue culture. Relative to early-passage lines, eight of nine late-passage hESC lines had one or more genomic alterations commonly observed in human cancers, including aberrations in copy number (45%), mitochondrial DNA sequence (22%) and gene promoter methylation (90%), although the latter was essentially restricted to 2 of 14 promoters examined. The observation that hESC lines maintained in vitro develop genetic and epigenetic alterations implies that periodic monitoring of these lines will be required before they are used in in vivo applications and that some late-passage hESC lines may be unusable for therapeutic purposes.
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