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

Autori
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.

Izvornik
Genome biology (1474-7596) 16 (2015), 1; 16, 15

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Hox genes ; glioblastoma

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA