Clone Phylogenetics Reveals Metastatic Tumor Migrations, Maps, and Models.

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.

Migrations of cancer cells through the lens of phylogenetic biogeography.

Malignant cells leave their initial tumor of growth and disperse to other tissues to form metastases. Dispersals also occur in nature when individuals in a population migrate from their area of origin to colonize other habitats. In cancer, phylogenetic biogeography is concerned with the source and trajectory of cell movements. We examine the suitability of primary features of organismal biogeography, including genetic diversification, dispersal, extinction, vicariance, and founder effects, to describe and reconstruct clone migration events among tumors. We used computer-simulated data to compare fits of seven biogeographic models and evaluate models' performance in clone migration reconstruction. Models considering founder effects and dispersals were often better fit for the clone phylogenetic patterns, especially for polyclonal seeding and reseeding of metastases. However, simpler biogeographic models produced more accurate estimates of cell migration histories. Analyses of empirical datasets of basal-like breast cancer had model fits consistent with the patterns seen in the analysis of computer-simulated datasets. Our analyses reveal the powers and pitfalls of biogeographic models for modeling and inferring clone migration histories using tumor genome variation data. We conclude that the principles of molecular evolution and organismal biogeography are useful in these endeavors but that the available models and methods need to be applied judiciously.

PathFinder: Bayesian inference of clone migration histories in cancer.

SUMMARY: Metastases cause a vast majority of cancer morbidity and mortality. Metastatic clones are formed by dispersal of cancer cells to secondary tissues, and are not medically detected or visible until later stages of cancer development. Clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations of cancer cells. Here, we present a new Bayesian approach, PathFinder, for reconstructing the routes of cancer cell migrations. PathFinder uses the clone phylogeny, the number of mutational differences among clones, and the information on the presence and absence of observed clones in primary and metastatic tumors. By analyzing simulated datasets, we found that PathFinder performes well in reconstructing clone migrations from the primary tumor to new metastases as well as between metastases. It was more challenging to trace migrations from metastases back to primary tumors. We found that a vast majority of errors can be corrected by sampling more clones per tumor, and by increasing the number of genetic variants assayed per clone. We also identified situations in which phylogenetic approaches alone are not sufficient to reconstruct migration routes.In conclusion, we anticipate that the use of PathFinder will enable a more reliable inference of migration histories and their posterior probabilities, which is required to assess the relative preponderance of seeding of new metastasis by clones from primary tumors and/or existing metastases. AVAILABILITY AND IMPLEMENTATION: PathFinder is available on the web at https://github.com/SayakaMiura/PathFinder.