De Novo Cancer Mutations Frequently Associate with Recurrent Chromosomal Abnormalities during Long-Term Human Pluripotent Stem Cell Culture

被引:3
作者
Al Delbany, Diana [1 ]
Ghosh, Manjusha S. [1 ]
Krivec, Nusa [1 ]
Huyghebaert, Anfien [1 ]
Regin, Marius [1 ]
Duong, Mai Chi [1 ,2 ]
Lei, Yingnan [1 ]
Sermon, Karen [1 ]
Olsen, Catharina [1 ,3 ,4 ]
Spits, Claudia [1 ]
机构
[1] Vrije Univ Brussel, Res Grp Genet Reprod & Dev, Laarbeeklaan 103, B-1090 Jette, Belgium
[2] Mil Hosp 175, Dept Biochem, 786 Nguyen Kiem St, Ho Chi Minh 71409, Vietnam
[3] ULB, VUB, Brussels Interuniv Genom High Throughput Core BRIG, Laarbeeklaan 101, B-1090 Brussels, Belgium
[4] VUB, ULB, Interuniv Inst Bioinformat Brussels, La Plaine Campus Triomflaan, B-1050 Brussels, Belgium
关键词
human pluripotent stem cells; genetic instability; copy number variation; single-nucleotide variants; cancer-related genes; IMPROVES; DIFFERENTIATION; DERIVATION; APOPTOSIS; 20Q11.21; DENSITY; LINES; GAIN;
D O I
10.3390/cells13161395
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Human pluripotent stem cells (hPSCs) are pivotal in regenerative medicine, yet their in vitro expansion often leads to genetic abnormalities, raising concerns about their safety in clinical applications. This study analyzed ten human embryonic stem cell lines across multiple passages to elucidate the dynamics of chromosomal abnormalities and single-nucleotide variants (SNVs) in 380 cancer-related genes. Prolonged in vitro culture resulted in 80% of the lines acquiring gains of chromosome 20q or 1q, both known for conferring an in vitro growth advantage. 70% of lines also acquired other copy number variants (CNVs) outside the recurrent set. Additionally, we detected 122 SNVs in 88 genes, with all lines acquiring at least one de novo SNV during culture. Our findings showed higher loads of both CNVs and SNVs at later passages, which were due to the cumulative acquisition of mutations over a longer time in culture, and not to an increased rate of mutagenesis over time. Importantly, we observed that SNVs and rare CNVs followed the acquisition of chromosomal gains in 1q and 20q, while most of the low-passage and genetically balanced samples were devoid of cancer-associated mutations. This suggests that recurrent chromosomal abnormalities are potential drivers for the acquisition of other mutations.
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页数:14
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