Metastasis Has Multiple Origins and Occurs Early in Tumorigenesis

Genetic studies of metastasis, the primary cause of cancer death, have been hindered in part by a lack of paired primary tumors and metastases available for research. In a study aiming to assess the natural history and clonal evolution of metastasis along with the effects of treatment, Hu and colleagues used 457 tumor samples from 136 patients (39 with colorectal cancer, 30 with lung cancer, and 67 with breast cancer), including 99 untreated metastases and 100 treated metastases. In each cancer type, the majority of clonal driver mutations were shared between primary tumors and metastases, whereas subclonal driver mutations were less commonly shared. Private clonal driver mutations were less common across all three cancer types, and less common still were such mutations in untreated metastases, implying that these metastases most often arise from a primary tumor's dominant clone. In contrast, private clonal drivers were found much more often in treated metastases, supporting the notion that clonal evolution is promoted by treatment. Further analysis revealed that the site of metastasis and treatment status were predictive of the prevalence of polyclonal seeding. For example, axillary lymph node metastases were more likely to be of polyclonal origin than distant metastases, perhaps due to multiple dissemination events from primary tumors to these nearby sites, and untreated distant metastases more often arose from polyclonal seeds than treated metastases, possibly reflecting treatment-induced selection. Consistent with the fact that metastasis-private clonal mutations were relatively rare, suggesting that metastatic seeding occurred early, computational modeling predicted that, on average, metastases were seeded two to four years prior to diagnosis of the primary tumor. Collectively, these findings provide meticulously detailed insight into the genetics underlying the metastatic process and highlight the importance of understanding how and when metastasis occurs to better design and apply treatments.

Hu Z, Li Z, Ma Z, Curtis C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat Genet 2020 May 18 [Epub ahead of print].

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