title: Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.
abstract: BACKGROUND
  HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma.
  
  
  RESULTS
  We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively.
  
  
  CONCLUSIONS
  Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. sebastian.kurscheid@anu.edu.au.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. sebastian.kurscheid@anu.edu.au.|Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. sebastian.kurscheid@anu.edu.au.|Present address: The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia. sebastian.kurscheid@anu.edu.au.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kurscheid
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.|Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. pierre.bady@unil.ch.|Department of Education and Research, University of Lausanne, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bady
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. davide.sciuscio@me.com.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. davide.sciuscio@me.com.
authors.forename: Davide
authors.initials: D
authors.lastname: Sciuscio
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. ivana_s@yahoo.com.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. ivana_s@yahoo.com.
authors.forename: Ivana
authors.initials: I
authors.lastname: Samarzija
authors.affiliation: Ben-Gurion University of the Negev, Beersheba, Israel. talshay@bgu.ac.il.
authors.forename: Tal
authors.initials: T
authors.lastname: Shay
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. irene.vassallo@chuv.ch.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. irene.vassallo@chuv.ch.
authors.forename: Irene
authors.initials: I
authors.lastname: Vassallo
authors.affiliation: Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium. wim.vancriekinge@gmail.com.
authors.forename: Wim V
authors.initials: WV
authors.lastname: Criekinge
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roy.daniel@chuv.ch.
authors.forename: Roy T
authors.initials: RT
authors.lastname: Daniel
authors.affiliation: Department of Neurology/Neurooncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands. m.vandenbent@erasmusmc.nl.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.affiliation: Department of Medicine, Medical University Vienna, Vienna, Austria. christine.marosi@meduniwien.ac.at.
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.affiliation: Department of Neurology, University of Tübingen, Tübingen, Germany. michael.weller@usz.ch.|Department of Neurology, University Hospital Zurich, Zurich, Switzerland. michael.weller@usz.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Princess Margaret Hospital, University of Toronto, Toronto, Canada. warren.mason@uhn.ca.
authors.forename: Warren P
authors.initials: WP
authors.lastname: Mason
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. eytan.domany@weizmann.ac.il.
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roger.stupp@usz.ch.|Department of Oncology, University Hospital Zurich, Zurich, 8091, Switzerland. roger.stupp@usz.ch.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. mauro.delorenzi@unil.ch.|Ludwig Center for Cancer Research, University of Lausanne, Lausanne, 1011, Switzerland. mauro.delorenzi@unil.ch.|Department of Oncology, University of Lausanne, Lausanne, 1011, Switzerland. mauro.delorenzi@unil.ch.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. monika.hegi@chuv.ch.|Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. monika.hegi@chuv.ch.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D018899:CpG Islands; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
chemical_list: D006657:Histones; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; C069634:HOXA10 protein, human