title: Inferring models of multiscale copy number evolution for single-tumor phylogenetics.
abstract: BACKGROUND
  Phylogenetic algorithms have begun to see widespread use in cancer research to reconstruct processes of evolution in tumor progression. Developing reliable phylogenies for tumor data requires quantitative models of cancer evolution that include the unusual genetic mechanisms by which tumors evolve, such as chromosome abnormalities, and allow for heterogeneity between tumor types and individual patients. Previous work on inferring phylogenies of single tumors by copy number evolution assumed models of uniform rates of genomic gain and loss across different genomic sites and scales, a substantial oversimplification necessitated by a lack of algorithms and quantitative parameters for fitting to more realistic tumor evolution models.
  
  
  RESULTS
  We propose a framework for inferring models of tumor progression from single-cell gene copy number data, including variable rates for different gain and loss events. We propose a new algorithm for identification of most parsimonious combinations of single gene and single chromosome events. We extend it via dynamic programming to include genome duplications. We implement an expectation maximization (EM)-like method to estimate mutation-specific and tumor-specific event rates concurrently with tree reconstruction. Application of our algorithms to real cervical cancer data identifies key genomic events in disease progression consistent with prior literature. Classification experiments on cervical and tongue cancer datasets lead to improved prediction accuracy for the metastasis of primary cervical cancers and for tongue cancer survival.
  
  
  METHODS
  Our software (FISHtrees) and two datasets are available at ftp://ftp.ncbi.nlm.nih.gov/pub/FISHtrees.
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Salim Akhter
authors.initials: SA
authors.lastname: Chowdhury
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Darawalee
authors.initials: D
authors.lastname: Wangsa
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heselmeyer-Haddad
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA Joint Carnegie Mellon/University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA, Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA, Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, USA, Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, USA and Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Schwartz
mesh_terms: D000465:Algorithms; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D018628:Gene Dosage; D023281:Genomics; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D010802:Phylogeny; D012984:Software; D002583:Uterine Cervical Neoplasms / Q000235:genetics