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Genome Biol. 2015 Jan 27;16:16. doi: 10.1186/s13059-015-0583-7.

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.

Author information

1
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. sebastian.kurscheid@anu.edu.au.
2
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. sebastian.kurscheid@anu.edu.au.
3
Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. sebastian.kurscheid@anu.edu.au.
4
Present address: The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia. sebastian.kurscheid@anu.edu.au.
5
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.
6
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.
7
Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. pierre.bady@unil.ch.
8
Department of Education and Research, University of Lausanne, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.
9
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. davide.sciuscio@me.com.
10
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. davide.sciuscio@me.com.
11
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. ivana_s@yahoo.com.
12
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. ivana_s@yahoo.com.
13
Ben-Gurion University of the Negev, Beersheba, Israel. talshay@bgu.ac.il.
14
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. irene.vassallo@chuv.ch.
15
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. irene.vassallo@chuv.ch.
16
Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium. wim.vancriekinge@gmail.com.
17
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roy.daniel@chuv.ch.
18
Department of Neurology/Neurooncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands. m.vandenbent@erasmusmc.nl.
19
Department of Medicine, Medical University Vienna, Vienna, Austria. christine.marosi@meduniwien.ac.at.
20
Department of Neurology, University of Tübingen, Tübingen, Germany. michael.weller@usz.ch.
21
Department of Neurology, University Hospital Zurich, Zurich, Switzerland. michael.weller@usz.ch.
22
Princess Margaret Hospital, University of Toronto, Toronto, Canada. warren.mason@uhn.ca.
23
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. eytan.domany@weizmann.ac.il.
24
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roger.stupp@usz.ch.
25
Department of Oncology, University Hospital Zurich, Zurich, 8091, Switzerland. roger.stupp@usz.ch.
26
Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. mauro.delorenzi@unil.ch.
27
Ludwig Center for Cancer Research, University of Lausanne, Lausanne, 1011, Switzerland. mauro.delorenzi@unil.ch.
28
Department of Oncology, University of Lausanne, Lausanne, 1011, Switzerland. mauro.delorenzi@unil.ch.
29
Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. monika.hegi@chuv.ch.
30
Neuroscience Research Center, Lausanne University Hospital, Lausanne, 1011, Switzerland. monika.hegi@chuv.ch.

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.

PMID:
25622821
PMCID:
PMC4342872
DOI:
10.1186/s13059-015-0583-7
[Indexed for MEDLINE]
Free PMC Article

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