文章：

对转移异质性泥沼的遗传学见解

Genetic insights into the morass of metastatic heterogeneity

原文发布日期：2018-02-09

DOI: 10.1038/nrc.2017.126

类型: Review Article

开放获取: 否

要点：

1. Metastasis heterogeneity within and between patients is a substantial problem for the clinical management of advanced cancer and has both genetic and nongenetic origins.
2. Recent advances in sequencing and acquisition of metastatic tissue are illuminating the phylogenetic relationship between primary tumours and metastases and the biology that underlies this evolutionary process.
3. Few recurrent metastasis-specific mutational driver events have been identified to date, highlighting the potential importance of other mechanisms, such as increased epigenetic plasticity, in metastatic progression.
4. Beyond heterogeneity in somatic tumour genetics, inherited germline polymorphisms may contribute substantially to differences in metastatic biology across populations.
5. Additional larger, well-controlled genomics studies using metastatic samples will be critical for a better understanding of the contribution of somatic heterogeneity to the clinical course of metastatic disease.

要点翻译：

1. 患者内部及患者之间的转移异质性是晚期癌症临床管理中的重大问题，其根源既包括遗传因素也包括非遗传因素。
2. 近年来，测序技术和转移组织获取技术的进展正在阐明原发性肿瘤与转移灶之间的系统发育关系，以及这一进化过程背后的生物学机制。
3. 迄今为止，仅发现少数反复出现的转移特异性突变驱动事件，这凸显了其他机制（如表观遗传可塑性增强）在转移进展中的潜在重要性。
4. 除体细胞肿瘤遗传学的异质性外，遗传性种系多态性可能对不同人群间转移生物学的差异产生重要影响。
5. 未来需要利用转移样本开展更多大规模、严格对照的基因组学研究，这对于深入理解体细胞异质性对转移性疾病临床进程的影响至关重要。

英文摘要：

Tumour heterogeneity poses a substantial problem for the clinical management of cancer. Somatic evolution of the cancer genome results in genetically distinct subclones in the primary tumour with different biological properties and therapeutic sensitivities. The problem of heterogeneity is compounded in metastatic disease owing to the complexity of the metastatic process and the multiple biological hurdles that the tumour cell must overcome to establish a clinically overt metastatic lesion. New advances in sequencing technology and clinical sample acquisition are providing insights into the phylogenetic relationship of metastases and primary tumours at the level of somatic tumour genetics while also illuminating fundamental mechanisms of the metastatic process. In addition to somatically acquired genetic heterogeneity in the tumour cells, inherited population-based genetic heterogeneity can profoundly modify metastatic biology and further complicate the development of effective, broadly applicable antimetastatic therapies. Here, we examine how genetic heterogeneity impacts metastatic disease and the implications of current knowledge for future research endeavours and therapeutic interventions.

摘要翻译： 

肿瘤异质性给癌症的临床管理带来了巨大挑战。原发瘤中癌症基因组的体细胞演化产生遗传背景不同的亚克隆，其生物学特性与治疗敏感性各异。由于转移过程复杂，肿瘤细胞必须跨越多重生物学屏障才能形成临床显性转移灶，异质性问题在转移性疾病中更为突出。新一代测序技术与临床样本获取手段的进步，不仅从体细胞遗传层面揭示了转移灶与原发瘤的系统发育关系，也阐明了转移过程的基本机制。除肿瘤细胞体细胞来源的遗传异质性外，人群水平的遗传性差异亦可显著调控转移生物学，并进一步阻碍广谱抗转移疗法的研发。本文综述了遗传异质性对转移性疾病的影响，并探讨当前认知对未来研究方向及治疗干预的启示。

原文链接：

Genetic insights into the morass of metastatic heterogeneity