19 research outputs found

    Evaluation of simulation methods for tumor subclonal reconstruction

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    Most neoplastic tumors originate from a single cell, and their evolution can be genetically traced through lineages characterized by common alterations such as small somatic mutations (SSMs), copy number alterations (CNAs), structural variants (SVs), and aneuploidies. Due to the complexity of these alterations in most tumors and the errors introduced by sequencing protocols and calling algorithms, tumor subclonal reconstruction algorithms are necessary to recapitulate the DNA sequence composition and tumor evolution in silico. With a growing number of these algorithms available, there is a pressing need for consistent and comprehensive benchmarking, which relies on realistic tumor sequencing generated by simulation tools. Here, we examine the current simulation methods, identifying their strengths and weaknesses, and provide recommendations for their improvement. Our review also explores potential new directions for research in this area. This work aims to serve as a resource for understanding and enhancing tumor genomic simulations, contributing to the advancement of the field

    Fast and scalable inference of multi-sample cancer lineages.

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    Somatic variants can be used as lineage markers for the phylogenetic reconstruction of cancer evolution. Since somatic phylogenetics is complicated by sample heterogeneity, novel specialized tree-building methods are required for cancer phylogeny reconstruction. We present LICHeE (Lineage Inference for Cancer Heterogeneity and Evolution), a novel method that automates the phylogenetic inference of cancer progression from multiple somatic samples. LICHeE uses variant allele frequencies of somatic single nucleotide variants obtained by deep sequencing to reconstruct multi-sample cell lineage trees and infer the subclonal composition of the samples. LICHeE is open source and available at http://viq854.github.io/lichee

    The copy-number tree mixture deconvolution problem and applications to multi-sample bulk sequencing tumor data

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    Cancer is an evolutionary process driven by somatic mutation. This process can be represented as a phylogenetic tree. Constructing such a phylogenetic tree from genome sequencing data is a challenging task due to the mutational complexity of cancer and the fact that nearly all cancer sequencing is of bulk tissue, measuring a super-position of somatic mutations present in different cells. We study the problem of reconstructing tumor phylogenies from copy number aberrations (CNAs) measured in bulk-sequencing data. We introduce the Copy-Number Tree Mixture Deconvolution (CNTMD) problem, which aims to find the phylogenetic tree with the fewest number of CNAs that explain the copy number data from multiple samples of a tumor. CNTMD generalizes two approaches that have been researched intensively in recent years: deconvolution/factorization algorithms that aim to infer the number and proportions of clones in a mixed tumor sample; and phylogenetic models of copy number evolution that model the dependencies between copy number events that affect the same genomic loci. We design an algorithm for solving the CNTMD problem and apply the algorithm to both simulated and real data. On simulated data, we find that our algorithm outperforms existing approaches that perform either deconvolution or phylogenetic tree construction under the assumption of a single tumor clone per sample. On real data, we analyze multiple samples from a prostate cancer patient, identifying clones within these samples and a phylogenetic tree that relates these clones and their differing proportions across samples. This phylogenetic tree provides a higher-resolution view of copy number evolution of this cancer than published analyses

    A Multi-labeled Tree Edit Distance for Comparing "Clonal Trees" of Tumor Progression

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    We introduce a new edit distance measure between a pair of "clonal trees", each representing the progression and mutational heterogeneity of a tumor sample, constructed by the use of single cell or bulk high throughput sequencing data. In a clonal tree, each vertex represents a specific tumor clone, and is labeled with one or more mutations in a way that each mutation is assigned to the oldest clone that harbors it. Given two clonal trees, our multi-labeled tree edit distance (MLTED) measure is defined as the minimum number of mutation/label deletions, (empty) leaf deletions, and vertex (clonal) expansions, applied in any order, to convert each of the two trees to the maximal common tree. We show that the MLTED measure can be computed efficiently in polynomial time and it captures the similarity between trees of different clonal granularity well. We have implemented our algorithm to compute MLTED exactly and applied it to a variety of data sets successfully. The source code of our method can be found in: https://github.com/khaled-rahman/leafDelTED

    Tree inference for single-cell data

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    Fast and scalable inference of multi-sample cancer lineages

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