title: FISHtrees 3.0: Tumor Phylogenetics Using a Ploidy Probe.
abstract: Advances in fluorescence in situ hybridization (FISH) make it feasible to detect multiple copy-number changes in hundreds of cells of solid tumors. Studies using FISH, sequencing, and other technologies have revealed substantial intra-tumor heterogeneity. The evolution of subclones in tumors may be modeled by phylogenies. Tumors often harbor aneuploid or polyploid cell populations. Using a FISH probe to estimate changes in ploidy can guide the creation of trees that model changes in ploidy and individual gene copy-number variations. We present FISHtrees 3.0, which implements a ploidy-based tree building method based on mixed integer linear programming (MILP). The ploidy-based modeling in FISHtrees includes a new formulation of the problem of merging trees for changes of a single gene into trees modeling changes in multiple genes and the ploidy. When multiple samples are collected from each patient, varying over time or tumor regions, it is useful to evaluate similarities in tumor progression among the samples. Therefore, we further implemented in FISHtrees 3.0 a new method to build consensus graphs for multiple samples. We validate FISHtrees 3.0 on a simulated data and on FISH data from paired cases of cervical primary and metastatic tumors and on paired breast ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Tests on simulated data show improved accuracy of the ploidy-based approach relative to prior ploidyless methods. Tests on real data further demonstrate novel insights these methods offer into tumor progression processes. Trees for DCIS samples are significantly less complex than trees for paired IDC samples. Consensus graphs show substantial divergence among most paired samples from both sets. Low consensus between DCIS and IDC trees may help explain the difficulty in finding biomarkers that predict which DCIS cases are at most risk to progress to IDC. The FISHtrees software is available at ftp://ftp.ncbi.nih.gov/pub/FISHtrees.
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: E Michael
authors.identifier: http://orcid.org/0000-0001-8390-4387
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, United States of America.|Carnegie Mellon/University of Pittsburgh Joint Ph.D. Program in Computational Biology, Pittsburgh, PA, United States of America.
authors.forename: Salim Akhter
authors.initials: SA
authors.lastname: Chowdhury
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Woei-Jyh
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Darawalee
authors.initials: D
authors.lastname: Wangsa
authors.affiliation: Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heselmeyer-Haddad
authors.affiliation: Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, National Cancer Institute, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States of America.|Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, United States of America.
authors.forename: Russell
authors.initials: R
authors.lastname: Schwartz
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, U.S. National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D030541:Databases, Genetic; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D011003:Ploidies; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor