Reconstructing tumor evolutionary histories and clone trees in polynomial-time with SubMARine

Abstract

Tumors contain multiple subpopulations of genetically distinct cancer cells. Reconstructing their evolutionary history can improve our understanding of how cancers develop and respond to treatment. Subclonal reconstruction methods cluster mutations into groups that co-occur within the same subpopulations, estimate the frequency of cells belonging to each subpopulation, and infer the ancestral relationships among the subpopulations by constructing a clone tree. However, often multiple clone trees are consistent with the data and current methods do not efficiently capture this uncertainty; nor can these methods scale to clone trees with a large number of subclonal populations. Here, we formalize the notion of a partial clone tree that defines a subset of the pairwise ancestral relationships in a clone tree, thereby implicitly representing the set of all clone trees that have these defined pairwise relationships. Also, we introduce a special partial clone tree, the Maximally-Constrained Ancestral Reconstruction (MAR), which summarizes all clone trees fitting the input data equally well. Finally, we extend commonly used clone tree validity conditions to apply to partial clone trees and describe SubMARine, a polynomial-time algorithm producing the subMAR, which approximates the MAR and guarantees that its defined relationships are a subset of those present in the MAR. We also extend SubMARine to work with subclonal copy number aberrations and define equivalence constraints for this purpose. In contrast with other clone tree reconstruction methods, SubMARine runs in time and space that scales polynomially in the number of subclones. We show through extensive simulation and a large lung cancer dataset that the subMAR equals the MAR in > 99.9% of cases where only a single clone tree exists and that it is a perfect match to the MAR in most of the other cases. Notably, SubMARine runs in less than 70 seconds on a single thread with less than one Gb of memory on all datasets presented in this paper, including ones with 50 nodes in a clone tree. The freely-available open-source code implementing SubMARine can be downloaded at https://github.com/morrislab/submarine. Author summaryCancer cells accumulate mutations over time and consist of genetically distinct subpopulations. Their evolutionary history (as represented by tumor phylogenies) can be inferred from bulk cancer genome sequencing data. Current tumor phylogeny reconstruction methods have two main issues: they are slow, and they do not efficiently represent uncertainty in the reconstruction. To address these issues, we developed SubMARine, a fast algorithm that summarizes all valid phylogenies in an intuitive format. SubMARine solved all reconstruction problems in this manuscript in less than 70 seconds, orders of magnitude faster than other methods. These reconstruction problems included those with up to 50 subclones; problems that are too large for other algorithms to even attempt. SubMARine achieves these result because, unlike other algorithms, it performs its reconstruction by identifying an upper-bound on the solution set of trees. In the vast majority of cases, this upper bound is tight: when only a single solution exists, SubMARine converges to it > 99.9% of the time; when multiple solutions exist, our algorithm correctly recovers the uncertain relationships in more than 80% of cases. In addition to solving these two major challenges, we introduce some useful new concepts for and open research problems in the field of tumor phylogeny reconstruction. Specifically, we formalize the concept of a partial clone tree which provides a set of constraints on the solution set of clone trees; and provide a complete set of conditions under which a partial clone tree is valid. These conditions guarantee that all trees in the solution set satisfy the constraints implied by the partial clone tree.