Abstract：
Gene amplifications have been known for several decades as physiological processes in amphibian and flies, e.g., during eggshell development in Drosophila and as part of pathological processes in humans, specifically in tumors and drug-resistant cells. The long-held belief that a physiological gene amplification does not occur in humans was, however, fundamental questioned by findings that showed gene amplification in human stem cells. We hypothesis that the physiological and the pathological, i.e., tumor associated processes of gene amplification share at their beginning the same underlying mechanism. Re-replication was reported both in the context of tumor related genome instability and during restricted time windows in Drosophila development causing the known developmental gene amplification in Drosophila. There is also growing evidence that gene amplification and re-replication were present in human stem cells. It appears likely that stem cells utilize a re-replication mechanism that has been developed early in evolution as a powerful tool to increase gene copy numbers very efficiently. Here, we show that, several decades ago, there was already evidence of gene amplification in non-tumor mammalian cells, but that was not recognized at the time and interpreted accordingly. We give an overview on gene amplifications during normal mammalian development, the possible mechanism that enable gene amplification and hypothesize how tumors adopted this capability for gene amplification.
摘要：
基因扩增作为两栖动物和果蝇的生理过程已经知道了几十年，例如，在果蝇的蛋壳发育过程中，作为人类病理过程的一部分，特别是在肿瘤和耐药细胞中。长期以来，人们一直认为生理基因扩增不会在人类中发生，然而,对人类干细胞中基因扩增的发现提出了基本质疑。我们假设生理和病理，即，肿瘤相关的基因扩增过程在开始时具有相同的潜在机制。在与肿瘤相关的基因组不稳定的背景下以及在果蝇发育的有限时间窗口期间都报道了重新复制，从而导致果蝇中已知的发育基因扩增。越来越多的证据表明，人类干细胞中存在基因扩增和重新复制。干细胞似乎利用在进化早期开发的再复制机制作为非常有效地增加基因拷贝数的强大工具。这里,我们证明，几十年前,已经有证据表明非肿瘤哺乳动物细胞中的基因扩增，但这在当时并没有得到承认，也没有得到相应的解释。我们概述了正常哺乳动物发育过程中的基因扩增，使基因扩增的可能机制，并假设肿瘤如何采用这种能力进行基因扩增。
