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Cancer Res. 2015 Oct 1;75(19):4021-5. doi: 10.1158/0008-5472.CAN-15-1889. Epub 2015 Aug 10.

Inferring the Origin of Metastases from Cancer Phylogenies.

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Yale School of Medicine, New Haven, Connecticut.
NeuroTexas Institute, St. David's Medical Center, Austin, Texas. Center for Systems and Synthetic Biology, University of Texas, Austin, Texas. Fresh Pond Research Institute, Cambridge, Massachusetts.
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut. Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut. Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.


Determining the evolutionary history of metastases is a key problem in cancer biology. Several recent studies have presented inferences regarding the origin of metastases based on phylogenies of cancer lineages. Many of these studies have concluded that the observed monophyly of metastatic subclones favored metastasis-to-metastasis spread ("a metastatic cascade" rather than parallel metastases from the primary tumor). In this article, we argue that identifying a monophyletic clade of metastatic subclones does not provide sufficient evidence to unequivocally establish a history of metastatic cascades. In the absence of a complete phylogeny of the subclones within the primary tumor, a scenario of parallel metastatic events from the primary tumor is an equally plausible interpretation. Future phylogenetic studies on the origin of metastases should obtain a complete phylogeny of subclones within the primary tumor. This complete phylogeny may be obtainable by ultra-deep sequencing and phasing of large sections or by targeted sequencing of many small, spatially heterogeneous sections, followed by phylogenetic reconstruction using well-established molecular evolutionary models. In addition to resolving the evolutionary history of metastases, a complete phylogeny of subclones within the primary tumor facilitates the identification of driver mutations by application of phylogeny-based tests of natural selection.

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