The challenges of tumor genetic diversity.
The challenges of tumor genetic diversity.
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DOI：
10.1002/cncr.30430
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发表时间：
2017-05-15
期刊：
影响因子：
6.2
通讯作者：
Rocco JW
中科院分区：
文献类型：
--
作者：
Mroz EA;Rocco JW
我们回顾和讨论了记录肿瘤多样性的基因组分析的含义，无论是在患者之间还是在单个肿瘤内。实体肿瘤的遗传多样性限制了靶向治疗，因为导致肿瘤的突变很少同时具有靶向性和高流行率。如果靶向治疗要变得广泛有效，就必须确定更多的驱动因素突变及其如何影响细胞信号通路。肿瘤内的遗传多样性，即肿瘤内的遗传异质性，使肿瘤成为一组亚克隆，相关但不同的癌症。通过常规或靶向治疗选择预先存在的耐药亚克隆可以解释许多治疗失败的原因。免疫疗法面临着同样的根本性挑战。然而，产生和维持异质性的过程可能提供新的治疗靶点。解决这两种类型的多样性需要与详细的临床数据相联系的基因组肿瘤分析。然而，对受限制的癌症基因面板进行测序的趋势限制了发现新的驱动因素突变和评估肿瘤内异质性的能力。目前通过基因组分析收集的临床数据往往缺乏关键信息，这大大限制了它们在了解肿瘤多样性方面的使用。既然肿瘤之间和肿瘤内的多样性不能再被忽视，研究和临床实践必须适应考虑到多样性。
We review and discuss the implications of genomic analyses documenting the diversity of tumors, both among patients and within individual tumors. Genetic diversity among solid tumors limits targeted therapies, as few mutations that drive tumors are both targetable and at high prevalence. Many more driver mutations and how they affect cellular signaling pathways must be identified if targeted therapy is to become widely useful. Genetic diversity within a tumor, intra-tumor genetic heterogeneity, makes the tumor a collection of subclones, related yet distinct cancers. Selection for pre-existing resistant subclones by conventional or targeted therapies may explain many treatment failures. Immune therapy faces the same fundamental challenges. Nevertheless, the processes that generate and maintain heterogeneity might provide novel therapeutic targets. Addressing both types of diversity requires genomic tumor analyses linked to detailed clinical data. The trend toward sequencing restricted cancer gene panels, however, limits the ability to discover new driver mutations and assess intra-tumor heterogeneity. Clinical data presently collected with genomic analyses often lack critical information, substantially limiting their use in understanding tumor diversity. Now that diversity among and within tumors can no longer be ignored, research and clinical practice must adapt to take diversity into account.