Abstract
Simple Summary Metastasis is the spread of cancer cells across organs and is a major cause of cancer mortality. Analysis of tumor sequencing data provides a means toward the reconstruction of routes of metastatic cell migrations. Our reconstructions demonstrated that many metastases were likely seeded from pre-existing metastasis of primary tumors. Additionally, multiple clone exchanges between tumor sites were common. In conclusion, the pattern of cancer cell migrations is often complex and is highly variable among patients. Dispersal routes of metastatic cells are not medically detected or even visible. A molecular evolutionary analysis of tumor variation provides a way to retrospectively infer metastatic migration histories and answer questions such as whether the majority of metastases are seeded from clones within primary tumors or seeded from clones within pre-existing metastases, as well as whether the evolution of metastases is generally consistent with any proposed models. We seek answers to these fundamental questions through a systematic patient-centric retrospective analysis that maps the dynamic evolutionary history of tumor cell migrations in many cancers. We analyzed tumor genetic heterogeneity in 51 cancer patients and found that most metastatic migration histories were best described by a hybrid of models of metastatic tumor evolution. Synthesizing across metastatic migration histories, we found new tumor seedings arising from clones of pre-existing metastases as often as they arose from clones from primary tumors. There were also many clone exchanges between the source and recipient tumors. Therefore, a molecular phylogenetic analysis of tumor variation provides a retrospective glimpse into general patterns of metastatic migration histories in cancer patients.