Reconstruction of clonal trees and tumor composition from multi-sample sequencing data

MOTIVATION DNA sequencing of multiple samples from the same tumor provides data to analyze the process of clonal evolution in the population of cells that give rise to a tumor. RESULTS We formalize the problem of reconstructing the clonal evolution of a tumor using single-nucleotide mutations as the variant allele frequency (VAF) factorization problem. We derive a combinatorial characterization of the solutions to this problem and show that the problem is NP-complete. We derive an integer linear programming solution to the VAF factorization problem in the case of error-free data and extend this solution to real data with a probabilistic model for errors. The resulting AncesTree algorithm is better able to identify ancestral relationships between individual mutations than existing approaches, particularly in ultra-deep sequencing data when high read counts for mutations yield high confidence VAFs. AVAILABILITY AND IMPLEMENTATION An implementation of AncesTree is available at: http://compbio.cs.brown.edu/software.