Fig. 1. Models and chronology of metastatic dissemination.

a Forward-time models and the chronology of metastatic dissemination. Metastasis occurs late in linear progression (either(I)—minor clone model or (II)—major clone model) and early in the parallel progression model (III). b Backward-time models and the chronology of metastatic dissemination. Metastasis commonly occurs several years prior to detection of the primary tumor, consistent with early dissemination from the major or dominant clone after emergence of the cancerous founder cell. c Driver gene heterogeneity in bulk sequencing of paired primary tumors and metastases under different models. In the minor clone model (I) of linear progression, metastases typically harbor “private” driver mutations which are present at low frequency in the primary tumor and undetectable in bulk sequencing. In contrast, the origin of metastasis from a major clone (II) typically leads to driver gene homogeneity. Parallel progression (III) characteristically leads to high driver gene heterogeneity where both the primary tumor and metastasis acquire private driver mutations after dissemination. Dx, diagnosis.