Genetic insights into the morass of metastatic heterogeneity

Abstract

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.

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

“…Metastasis remains poorly understood despite its critical clinical importance. For instance, metastases have been reported to originate from a single cell or clone in the primary tumor (monoclonal seeding) [1][2][3][4] or multiple clones (polyclonal seeding) [5][6][7] , but the prevalence of these patterns across distinct tumor types is unknown as is the impact of therapy and the timing of metastatic seeding [8][9][10] . While several recent studies have genomically characterized metastatic lesions [11][12][13] in the absence of the matched primary tumor, it is not feasible to disentangle the drivers of metastasis from those that are treatment associated since metastases are often sampled after treatment.…”

“…While several recent studies have genomically characterized metastatic lesions [11][12][13] in the absence of the matched primary tumor, it is not feasible to disentangle the drivers of metastasis from those that are treatment associated since metastases are often sampled after treatment. However, comparisons of paired primary tumors and metastases have been far more limited due to the challenge in obtaining such samples 5,8,[14][15][16][17][18] . As such, there has yet to be a systematic analysis of monoclonal versus polyclonal seeding, the chronology of systemic spread and the effect of therapy across cancers.…”

Single-cell RNA-seq reveals that glioblastoma recapitulates normal brain development

“…Significant obstacles hampering the development of effective cancer therapeutics include tumour heterogeneity [1][2][3][4][5] , and the persistence of poorly understood cancer stem cells (CSCs) that give rise to cancer recurrence 6,7 .…”

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…As one reads the literature, it is critical to remember that the mitochondrial genome changes are likely metastasis modifiers rather than drivers per se . In other words, mtDNA encodes quantitative trait loci (QTL) that combine with both nuclear and mitochondrially-encoded genes to regulate complex diseases like cancer and disease severity [49–51]. QTL are a group of alleles that influence a particular phenotype or trait [52].…”