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.

肿瘤异质性对癌症的临床管理提出了实质性的问题。癌症基因组的体细胞进化导致原发肿瘤在遗传上不同的亚克隆具有不同的生物学特性和治疗敏感性。由于转移过程的复杂性以及肿瘤细胞必须克服的多个生物学障碍才能建立临床上明显的转移性病灶，因此异质性问题在转移性疾病中更为复杂。测序技术和临床样品采集方面的新进展为我们提供了从体细胞肿瘤遗传学层面深入了解转移灶和原发肿瘤的系统发生关系的见解，同时也阐明了转移过程的基本机制。除了在肿瘤细胞中获得体细胞遗传异质性外，基于人群的遗传遗传异质性可以深刻地改变转移生物学，并进一步使有效，广泛适用的抗转移疗法的发展复杂化。在这里，我们研究了遗传异质性如何影响转移性疾病以及当前知识对未来研究和治疗干预的影响。