Gene amplifications in tumor cells:newly developed or adapted from normal cells?

基因扩增是人类肿瘤的一个标志，并对几种癌症患者的预后有影响。到目前为止，正常发育过程中的基因扩增只在两栖动物和苍蝇身上发现。我第一次获得资助期间的数据表明，基因扩增也可以发生在正常的哺乳动物细胞中。具体来说，在人和小鼠神经祖细胞分化过程中，可以检测到全基因组基因扩增。值得注意的是，大约50%的小鼠扩增染色体区域在人类中也被检测到。此外，许多这些扩增的染色体区域与人类胶质母细胞瘤中扩增的染色体区域重叠。与人类肿瘤细胞中的基因扩增相比，人类和小鼠神经祖细胞的基因扩增似乎只发生在一小部分细胞的一小段时间内。基于这些数据，出现了以下问题：在分化过程中，基因扩增在神经干细胞以外的其他细胞中是否可检测到？是否有证据表明基因扩增是哺乳动物细胞分化过程中的一种常见现象？扩增的DNA和携带扩增物的细胞的命运如何？神经祖细胞中扩增DNA的基因组组织是什么？这些基因组结构是否支持或反驳基因扩增起源的已知模型？

Gene amplification is a hallmark of human tumors and has an impact on patients prognosis in several cancers. As of now, gene amplifications during normal development are only known from amphibians and flies. The data from my first grant period show that gene amplifications can also occur in normal mammalian cells. Specifically, during differentiation of human and mouse neural progenitor cells genome-wide gene amplifications were detectable. Notably, about 50% of the mouse amplified chromosome regions were also detected in human. In addition, many of these amplified chromosomal regions overlap with chromosomal regions amplified in human glioblastoma. In contrast to gene amplifications in human tumor cells, gene amplifications of human and mouse neural progenitor cells appear to occur only during a small time-window in a small number of cells. Based on these data, the following questions arise:Are gene amplifications detectable in other cells than neural stem cells during differentiation? Is there evidence for gene amplification being a frequent phenomenon during differentiation in mammalian cells? What is the fate of the amplified DNA and of the cells that harbor amplifications? What is the genomic organization of the amplified DNA in neural progenitor cells and can known models of the origin of gene amplification be supported or disproved by these genomic structures?