Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
Neurosurg Focus. 2010 Jan;28(1):E5. doi: 10.3171/2009.10.FOCUS09212.
Our understanding of glioblastoma multiforme (GBM), the most common form of primary brain cancer, has been significantly advanced by recent efforts to characterize the cancer genome using unbiased high-throughput sequencing analyses. While these studies have documented hundreds of mutations, gene copy alterations, and chromosomal abnormalities, only a subset of these alterations are likely to impact tumor initiation or maintenance. Furthermore, genes that are not altered at the genomic level may play essential roles in tumor initiation and maintenance. Identification of these genes is critical for therapeutic development and investigative methodologies that afford insight into biological function. This requirement has largely been fulfilled with the emergence of RNA interference (RNAi) and high-throughput screening technology. In this article, the authors discuss the application of genome-wide, high-throughput RNAi-based genetic screening as a powerful tool for the rapid and cost-effective identification of genes essential for cancer proliferation and survival. They describe how these technologies have been used to identify genes that are themselves selectively lethal to cancer cells, or synthetically lethal with other oncogenic mutations. The article is intended to provide a platform for how RNAi libraries might contribute to uncovering glioma cell vulnerabilities and provide information that is highly complementary to the structural characterization of the glioblastoma genome. The authors emphasize that unbiased, systems-level structural and functional genetic approaches are complementary efforts that should facilitate the identification of genes involved in the pathogenesis of GBM and permit the identification of novel drug targets.
我们对胶质母细胞瘤（GBM）的认识，即最常见的原发性脑癌形式，通过使用无偏高通量测序分析来描述癌症基因组的最新努力得到了显著提高。虽然这些研究已经记录了数百种突变、基因拷贝改变和染色体异常，但只有一小部分改变可能会影响肿瘤的起始或维持。此外，在基因组水平上没有改变的基因可能在肿瘤起始和维持中发挥重要作用。鉴定这些基因对于治疗开发和提供对生物学功能的深入了解的研究方法至关重要。这一要求在 RNA 干扰 (RNAi) 和高通量筛选技术的出现后基本得到满足。在本文中，作者讨论了基于全基因组、高通量 RNAi 的遗传筛选作为一种快速、经济有效地鉴定癌症增殖和存活所必需基因的强大工具的应用。他们描述了如何使用这些技术来鉴定对癌细胞本身具有选择性致死性或与其他致癌突变具有合成致死性的基因。本文旨在为 RNAi 文库如何有助于揭示神经胶质瘤细胞的脆弱性提供一个平台，并提供与胶质母细胞瘤基因组结构特征高度互补的信息。作者强调，无偏、系统水平的结构和功能遗传方法是相辅相成的努力，这将有助于鉴定参与 GBM 发病机制的基因，并允许鉴定新的药物靶点。
