New Oncology, Blackfield AG, Cologne.
Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
Ann Oncol. 2015 Sep;26(9):1830-1837. doi: 10.1093/annonc/mdv184. Epub 2015 Apr 21.
The identification of 'druggable' kinase gene alterations has revolutionized cancer treatment in the last decade by providing new and successfully targetable drug targets. Thus, genotyping tumors for matching the right patients with the right drugs have become a clinical routine. Today, advances in sequencing technology and computational genome analyses enable the discovery of a constantly growing number of genome alterations relevant for clinical decision making. As a consequence, several technological approaches have emerged in order to deal with these rapidly increasing demands for clinical cancer genome analyses. Here, we describe challenges on the path to the broad introduction of diagnostic cancer genome analyses and the technologies that can be applied to overcome them. We define three generations of molecular diagnostics that are in clinical use. The latest generation of these approaches involves deep and thus, highly sensitive sequencing of all therapeutically relevant types of genome alterations-mutations, copy number alterations and rearrangements/fusions-in a single assay. Such approaches therefore have substantial advantages (less time and less tissue required) over PCR-based methods that typically have to be combined with fluorescence in situ hybridization for detection of gene amplifications and fusions. Since these new technologies work reliably on routine diagnostic formalin-fixed, paraffin-embedded specimens, they can help expedite the broad introduction of personalized cancer therapy into the clinic by providing comprehensive, sensitive and accurate cancer genome diagnoses in 'real-time'.
在过去的十年中，通过提供新的、成功的靶向药物靶点，识别“可成药”激酶基因突变彻底改变了癌症治疗。因此，对肿瘤进行基因分型以将合适的患者与合适的药物相匹配已成为临床常规。如今，测序技术和计算基因组分析的进步使发现越来越多与临床决策相关的基因组改变成为可能。因此，为了满足临床癌症基因组分析的快速增长需求，出现了几种技术方法。在这里，我们描述了在广泛引入诊断性癌症基因组分析的道路上面临的挑战，以及可以应用于克服这些挑战的技术。我们定义了正在临床应用的三代分子诊断方法。这些方法的最新一代涉及对所有治疗相关类型的基因组改变（突变、拷贝数改变和重排/融合）进行深度测序，即高度敏感的测序。与通常必须与荧光原位杂交结合以检测基因扩增和融合的基于 PCR 的方法相比，这种方法具有实质性的优势（所需时间和组织更少）。由于这些新技术可在常规的诊断性福尔马林固定、石蜡包埋标本上可靠地工作，因此通过提供全面、敏感和准确的癌症基因组诊断，它们可以帮助加速个性化癌症治疗在临床上的广泛应用，实现“实时”癌症基因组诊断。
