title: Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies.
abstract: Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation.
  
  
  
  To distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single-cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers.
  
  
  
  Our data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification.
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Bakker
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Taudt
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.|Department of Paediatrics, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Mirjam E
authors.initials: ME
authors.lastname: Belderbos
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Porubsky
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Diana C J
authors.initials: DC
authors.lastname: Spierings
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Tristan V
authors.initials: TV
authors.lastname: de Jong
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Nancy
authors.initials: N
authors.lastname: Halsema
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Hinke G
authors.initials: HG
authors.lastname: Kazemier
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Karina
authors.initials: K
authors.lastname: Hoekstra-Wakker
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Department of Paediatrics, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.affiliation: Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.|Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.|Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands. maria.colome@helmholtz-muenchen.de.|Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. maria.colome@helmholtz-muenchen.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Colomé-Tatché
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands. f.foijer@umcg.nl.
authors.forename: Floris
authors.initials: F
authors.lastname: Foijer
mesh_terms: D000782:Aneuploidy; D000818:Animals; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D056915:DNA Copy Number Variations; D018740:Genetic Heterogeneity; D006801:Humans; D059785:Karyotype; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D059010:Single-Cell Analysis / Q000379:methods; D012984:Software
keywords: Aneuploidy; Copy number detection; Karyotype heterogeneity; Leukaemia; Lymphoma; Single-cell sequencing