人类多能干细胞经常获得和扩展主导的负P53突变
Florian T Merkle1,2,3,4, Sulagna Ghosh1,2,3,4, Nolan Kamitaki3,5,6
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Nature
|April 27, 2017
概括
培养的人类多能干细胞 (hPS细胞) 可以获得与癌症相关的TP53突变,从而具有增长优势. 在临床使用这些有价值的干细胞之前,
科学领域:
- 干细胞生物学
- 遗传学
- 癌症研究
背景情况:
- 人类多能干细胞 (hPS细胞) 对于再生医学至关重要,因为它们具有自我更新的能力.
- 培养的hPS细胞可以积累遗传突变,包括拷贝数变异,可能会影响它们的安全性.
- 在hPS细胞中,除拷贝数变异之外的获得突变的范围仍然很大程度上是未知的.
研究的目的:
- 在培养的人类胚胎干细胞 (hES) 线上研究获得的基因组序列突变的性质和功能影响.
- 在hPS细胞系中发现与癌症相关的突变,特别是那些用于临床应用的突变.
- 评估hPS细胞中TP53突变的流行率和选择性优势.
主要方法:
- 140个独立的hES细胞系的外体序列.
- 计算分析检测细胞系内的马赛克突变.
- 从117个hPS细胞系中挖掘已发表的RNA测序数据.
- 对TP53突变等位素分数及其与通道数的相关性进行分析.
主要成果:
- 在五个无关hES细胞系中发现了六种TP53突变,所有突变都编码了人类癌症中常见的主导负变异.
- 突变TP53的基因分数随着通路数增加而增加,这表明有选择性的生长优势.
- 在其他hPS细胞系中发现了另外9个TP53突变,影响了P53的DNA结合域.
- 在三条线中观察到TP53位点的异构性损失,进一步增强了选择性优势.
结论:
- 在标准培养条件下,培养的hPS细胞可以获得和扩展与癌症相关的TP53突变.
- 这些突变可能会带来选择性优势,可能会被忽视.
- 在临床应用之前,对hPS细胞及其衍生物进行严格的基因鉴定是必不可少的,以确保患者的安全.
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