Stevens Joshua B, Horne Steven D, Abdallah Batoul Y, Ye Christine J, Heng Henry H
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
Cancer Metastasis Rev. 2013 Dec;32(3-4):391-402. doi: 10.1007/s10555-013-9428-6.
Whole transcriptome profiling has long been proposed as a method of identifying cancer-specific gene expression profiles. Indeed, a multitude of these studies have generated vast amounts of expression data for many types of cancer, and most have identified specific gene signatures associated with a given cancer. These studies however, often contradict with each other, and gene lists only rarely overlap, challenging clinical application of cancer gene signatures. To understand this issue, the biological basis of transcriptome dynamics needs to be addressed. Chromosome instability (CIN) is the main contributor to genome heterogeneity and system dynamics, therefore the relationship between CIN, genome heterogeneity, and transcriptome dynamics has important implications for cancer research. In this review, we discuss CIN and its effects on the transcriptome during cancer progression, specifically how stochastic chromosome change results in transcriptome dynamics. This discussion is further applied to metastasis and drug resistance both of which have been linked to multiple diverse molecular mechanisms but are in fact driven by CIN. The diverse molecular mechanisms that drive each process are linked to karyotypic heterogeneity through the evolutionary mechanism of cancer. Karyotypic change and the resultant transcriptome change alter network function within cells increasing the evolutionary potential of the tumor. Future studies must embrace this instability-induced heterogeneity in order to devise new research and treatment modalities that focus on the evolutionary process of cancer rather than the individual genes that are uniquely changed in each tumor. Care is also needed in evaluating results from experimental systems which measure average values of a population.
全转录组分析长期以来一直被提议作为一种识别癌症特异性基因表达谱的方法。事实上，众多此类研究已经为多种癌症生成了大量的表达数据，并且大多数研究都确定了与特定癌症相关的特定基因特征。然而，这些研究往往相互矛盾，基因列表很少重叠，这对癌症基因特征的临床应用构成了挑战。为了理解这个问题，需要探讨转录组动态变化的生物学基础。染色体不稳定性（CIN）是基因组异质性和系统动态变化的主要原因，因此CIN、基因组异质性和转录组动态变化之间的关系对癌症研究具有重要意义。在这篇综述中，我们讨论CIN及其在癌症进展过程中对转录组的影响，特别是随机染色体变化如何导致转录组动态变化。这一讨论进一步应用于转移和耐药性，这两者都与多种不同的分子机制有关，但实际上是由CIN驱动的。驱动每个过程的多种分子机制通过癌症的进化机制与核型异质性相关联。核型变化和由此产生的转录组变化改变了细胞内的网络功能，增加了肿瘤的进化潜力。未来的研究必须接受这种由不稳定性引起的异质性，以便设计出新的研究和治疗模式，这些模式关注癌症的进化过程而非每个肿瘤中独特变化的个别基因。在评估测量群体平均值的实验系统结果时也需要谨慎。
