Kurscheid, SebastianBady, PierreSciuscio, DavideSamarzija, IvanaShay, TalVassallo, IreneCriekinge, Wim V.Daniel, Roy T.van den Bent, Martin J.Marosi, ChristineWeller, MichaelMason, Warren P.Domany, EytanStupp, RogerDelorenzi, MauroHegi, Monika E.2015-04-302015-04-301465-6906http://hdl.handle.net/1885/13356BACKGROUND: 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.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.15 pages© 2015 Kurscheid et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Keywords: DNA; histone; microRNA; RNA; transcription factor HoxA10; Article; cancer tissue; chromatin; chromatin immunoprecipitation; chromosome 7; CpG island; DNA methylation; gene dosage; gene expression; gene locus; glioblastoma; HOXA10 gene; human; human tissue2015-01-2710.1186/s13059-015-0583-72018-11-29