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

• Published in: Genome Biology 2015-01, Vol.16 (1), p.16, Article 16
• Main Authors: Kurscheid, Sebastian, Bady, Pierre, Sciuscio, Davide, Samarzija, Ivana, Shay, Tal, Vassallo, Irene, Criekinge, Wim V, Daniel, Roy T, van den Bent, Martin J, Marosi, Christine, Weller, Michael, Mason, Warren P, Domany, Eytan, Stupp, Roger, Delorenzi, Mauro, Hegi, Monika E
• Format: Article
• Language: English
• Subjects: Bioinformatics; Brain - metabolism; Brain - pathology; Brain cancer; Brain research; Brain tumors; Cancer therapies; Cell Line, Tumor; Cell proliferation; Chemotherapy; Chromatin; Chromosome 7; Chromosomes, Human, Pair 7 - genetics; Cluster analysis; CpG Islands; Databases, Genetic; Deoxyribonucleic acid; DNA; DNA Copy Number Variations - genetics; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; Epigenetics; Forebrain; Gene dosage; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Loci; Genome, Human; Genomes; Glioblastoma; Glioblastoma - genetics; Glioma cells; Histones - metabolism; Homeodomain Proteins - genetics; Humans; Linear Models; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Promoter Regions, Genetic; Radiation therapy; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Transcription; Transcriptome - genetics
• ISSN: 1465-6906; 1474-7596; 1474-760X; 1465-6906; 1465-6914
• DOI: 10.1186/s13059-015-0583-7

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. 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. 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.