MOTIVATION: Discovering the evolution of a tumor may help identify driver mutations and provide a more comprehensive view on the history of the tumor. Recent studies have tackled this problem using multiple samples sequenced from a tumor, and due to clinical implications, this has attracted great interest. However, such samples usually mix several distinct tumor subclones, which confounds the discovery of the tumor phylogeny. RESULTS: We study a natural problem formulation requiring to decompose the tumor samples into several subclones with the objective of forming a minimum perfect phylogeny. We propose an Integer Linear Programming formulation for it, and implement it into a method called MIPUP. We tested the ability of MIPUP and of four popular tools LICHeE, AncesTree, CITUP, Treeomics to reconstruct the tumor phylogeny. On simulated data, MIPUP shows up to a 34% improvement under the ancestor-descendant relations metric. On four real datasets, MIPUP's reconstructions proved to be generally more faithful than those of LICHeE. AVAILABILITY AND IMPLEMENTATION: MIPUP is available at https://github.com/zhero9/MIPUP as open source. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Motivated by applications in cancer genomics and following the work of Hajirasouliha and Raphael (WABI 2014), Hujdurović et al. (IEEE TCBB, 2018) introduced the minimum conflict-free row split (MCRS) problem: split each row of a given binary matrix into a bitwise OR of a set of rows so that the resulting matrix corresponds to a perfect phylogeny and has the minimum possible number of rows among all matrices with this property. Hajirasouliha and Raphael also proposed the study of a similar problem, in which the task is to minimize the number of distinct rows of the resulting matrix. Hujdurović et al. proved that both problems are NP-hard, gave a related characterization of transitively orientable graphs, and proposed a polynomial-time heuristic algorithm for the MCRS problem based on coloring cocomparability graphs. We give new, more transparent formulations of the two problems, showing that the problems are equivalent to two optimization problems on branchings in a derived directed acyclic graph. Building on these formulations, we obtain new results on the two problems, including (1) a strengthening of the heuristic by Hujdurović et al. via a new min-max result in digraphs generalizing Dilworth’s theorem, which may be of independent interest; (2) APX-hardness results for both problems; (3) approximation algorithms; and (4) exponential-time algorithms solving the two problems to optimality faster than the naïve brute-force approach. Our work relates to several well-studied notions in combinatorial optimization: chain partitions in partially ordered sets, laminar hypergraphs, and (classical and weighted) colorings of graphs.

Hajirasouliha and Raphael (WABI 2014) proposed a model for deconvoluting mixed tumor samples measured from a collection of high-throughput sequencing reads. This is related to understanding tumor evolution and critical cancer mutations. In short, their formulation asks to split each row of a binary matrix so that the resulting matrix corresponds to a perfect phylogeny and has the minimum number of rows among all matrices with this property. In this paper, we disprove several claims about this problem, including an NP-hardness proof of it. However, we show that the problem is indeed NP-hard, by providing a different proof. We also prove NP-completeness of a variant of this problem proposed in the same paper. On the positive side, we propose an efficient (though not necessarily optimal) heuristic algorithm based on coloring co-comparability graphs, and a polynomial time algorithm for solving the problem optimally on matrix instances in which no column is contained in both columns of a pair of conflicting columns. Implementations of these algorithms are freely available at https://github.com/alexandrutomescu/MixedPerfectPhylogeny.