Inferring the Origin of Metastases from Cancer Phylogenies

Abstract

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.

Figure 1

Figure 1a. Assume that the subclones A and E are the most common in the primary tumor, while F and G are rarer and are not sampled, and that there is a unique primary tumor metastasis from which later metastastic subclones (B, C, and D) are derived. Figure 1b. This case makes similar assumptions about sampling as in 1a, except that parallel metastases are independently derived from the lineage containing the rarer (unsampled) subclones F and G. Figure 1c. Metastatic tumor subclades B–D are derived from polyphyletic subclonal lineages in the primary tumor.

Figure 2

Phylogenies of the first three subjects from Hong et al.[6] (a: Subject 299, b: Subject 498, c: Subject 177). These phylogenetic trees are not the result of a new analysis. They are a preferred graphical representation to those presented in Hong et al.[6] that is topologically equivalent. In this depiction, observed subclones are represented as terminal taxa (leaves) rather than as direct ancestors (internal nodes). The topologies of the phylogenetic relationships among subclones shown here are entirely equivalent to the topologies presented in Hong et al.[6].