Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.
- Kurscheid S Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. sebastian.kurscheid@anu.edu.au.
- Bady P Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. pierre.bady@unil.ch.
- Sciuscio D Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. davide.sciuscio@me.com.
- Samarzija I Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. ivana_s@yahoo.com.
- Shay T Ben-Gurion University of the Negev, Beersheba, Israel. talshay@bgu.ac.il.
- Vassallo I Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. irene.vassallo@chuv.ch.
- Criekinge WV Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium. wim.vancriekinge@gmail.com.
- Daniel RT Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roy.daniel@chuv.ch.
- van den Bent MJ Department of Neurology/Neurooncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands. m.vandenbent@erasmusmc.nl.
- Marosi C Department of Medicine, Medical University Vienna, Vienna, Austria. christine.marosi@meduniwien.ac.at.
- Weller M Department of Neurology, University of Tübingen, Tübingen, Germany. michael.weller@usz.ch.
- Mason WP Princess Margaret Hospital, University of Toronto, Toronto, Canada. warren.mason@uhn.ca.
- Domany E Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. eytan.domany@weizmann.ac.il.
- Stupp R Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. roger.stupp@usz.ch.
- Delorenzi M Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 1005, Switzerland. mauro.delorenzi@unil.ch.
- Hegi ME Neurosurgery, Lausanne University Hospital, Lausanne, 1011, Switzerland. monika.hegi@chuv.ch.
- 2015-01-28
Published in:
- Genome biology. - 2015
Brain
Cell Line, Tumor
Chromosomes, Human, Pair 7
CpG Islands
DNA Copy Number Variations
DNA Methylation
Databases, Genetic
Epigenesis, Genetic
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Loci
Genome, Human
Glioblastoma
Histones
Homeobox A10 Proteins
Homeodomain Proteins
Humans
Linear Models
MicroRNAs
Neoplastic Stem Cells
Promoter Regions, Genetic
Spheroids, Cellular
Transcriptome
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13059-015-0583-7
- PMID 25622821
- Persistent URL
- https://sonar.ch/global/documents/20335
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