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

Sebastian Kurscheid; Pierre Bady; Davide Sciuscio; Ivana Samarzija; Tal Shay; Irene Vassallo; Wim V. Criekinge; Roy T. Daniel; den Bent, Martin J. van den Bent; Christine Marosi; Michael Weller; Warren P. Mason; Eytan Domany; Roger Stupp; Mauro Delorenzi; Monika E. Hegi

doi:10.1186/s13059-015-0583-7

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

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

Sebastian Kurscheid, Pierre Bady, Davide Sciuscio, Ivana Samarzija, Tal Shay, Irene Vassallo, Wim V. Criekinge, Roy T. Daniel, den Bent, Martin J. van den Bent, Christine Marosi, …

Genome Biology, Vol.16, 16

27/Jan/2015

DOI: https://doi.org/10.1186/s13059-015-0583-7

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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.

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Title: Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma
Creators: Sebastian Kurscheid (null) - University Hospital of Lausanne
Pierre Bady (null) - University Hospital of Lausanne
Davide Sciuscio (null) - University Hospital of Lausanne
Ivana Samarzija (null) - University Hospital of Lausanne
Tal Shay (null) - Ben-Gurion University of the Negev
Irene Vassallo (null) - University Hospital of Lausanne
Wim V. Criekinge (null) - Ghent University
Roy T. Daniel (null) - University Hospital of Lausanne
den Bent, Martin J. van den Bent (null) - Erasmus MC Cancer Institute
Christine Marosi (null) - Medical University of Vienna
Michael Weller (null) - University of Tübingen
Warren P. Mason (null) - Princess Margaret Cancer Centre (Canada, Toronto)
Eytan Domany (null) - 972WIS_INST___89
Roger Stupp (null) - University Hospital of Lausanne
Mauro Delorenzi (null) - SIB Swiss Institute of Bioinformatics
Monika E. Hegi (Corresponding Author) - University Hospital of Lausanne
Resource Type: Journal article
Publication Details: Genome Biology, Vol.16, 16; 27/Jan/2015
Number of pages: 15
Language: English
DOI: https://doi.org/10.1186/s13059-015-0583-7
Grant note: Swiss National Science Foundation [3100A-138116]; National Center of Competence in Research Molecular Oncology; Swiss Cancer League [KFS-29-02-2012]; Leir Charitable Foundation. This work was supported by the Swiss National Science Foundation (3100A-138116), the National Center of Competence in Research Molecular Oncology, and the Swiss Cancer League (KFS-29-02-2012). The work of TS and ED was supported in part by a grant from the Leir Charitable Foundation. The results published here are in part based upon data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/publications/publicationguidelines. SK participated in the statistical analysis of all datasets and design of the study, performed the bioinformatics analysis of sequencing data, and drafted the manuscript. PB designed and participated in the statistical analysis. DS participated in ChIP-qPCR and MS-Clone-Sequencing experiments of gliomaspheres. IS performed laboratory part of RNA-Seq experiment. TS performed statistical analysis related to correlation of copy number and gene expression in EORTC_NCH dataset. WvC coordinated RNA-Seq experiments and helped to draft the manuscript. IV participated in ChIP-qPCR experiments. RTD, MJB, CM, WPM, and RS participated in collection and assembly of data. ED and MD provided statistical and bioinformatics support. MEH conceived of the study, and participated in its design and coordination, and drafted the manuscript. All authors read and approved the final manuscript._ALMAME_DELIMITER_
Record Identifier: 993262896903596

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