Genetic insights into the morass of metastatic heterogeneity

Key Points Metastasis heterogeneity within and between patients is a substantial problem for the clinical management of advanced cancer and has both genetic and nongenetic origins. 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. 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. Beyond heterogeneity in somatic tumour genetics, inherited germline polymorphisms may contribute substantially to differences in metastatic biology across populations. 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. In this Review, Hunter et al . discuss how genetic heterogeneity impacts metastatic disease and outline the implications of our current knowledge in this area for future research efforts and therapeutic interventions. 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.