Abstract 3387: Upregulation of gene expression in oligodendrogliomas is linked to an increase in GA binding protein alpha transcription
Authors: Klink Barbara , Szafranski Karol , Campos-Valenzuela Jaime , Eisenreich Sophie , Krex Dietmar , Gerlach Eva-Maria , Hackmann Karl , Rump Andreas , Schackert Gabriele , Platzer Matthias , Kaderali Lars , Schröck Evelin , Abou-El-Ardat Khalil 
Published: May 2015

Lower grade gliomas can be histologically classified into astrocytomas, oligoastrocytomas, or oligodendrogliomas. The latter have come into focus because of their interesting characteristics: they have a more favorable outcome and better response to chemo/radiotherapy. This is correlated with a unique unbalanced translocation der(1;19)(q10;p10) causing a codeletion of the short arm of chromosome 1 and the long arm of chromosome 19. Like the other lower grade gliomas, a large percentage of oligodendrogliomas carry the IDH1 R132 mutation and this is associated with the presence of the codeletion. We identified a high number of mutations in the remaining alleles of the Capicua homolog gene (CIC) and in the far upstream element binding protein (FUBP1) in 1p/19q codeleted oligodendrogliomas (Eisenreich et al. 2013, doi:10.1371/journal.pone.0076623). Both genes are suspected to act as tumor suppressor genes. We then analyzed the expression profiles of 13 oligodendrogliomas and oligoastrocytomas both with the 1p/19q codeletion (nine samples) and without (four samples) using a combination of expression microarrays and transcriptome sequencing (RNA-Seq). Our results showed that all nine samples with the 1p/19q codeletion carried the heterozygous IDH1 R132H mutation while only one tumor without the codeletion carried said mutation. There was a high concordance between the results of RNA-Seq and the microarray experiments and both showed a distinctive expression signature between samples with the 1p/19q codeletion and those without. Using MSigDB, we found that the genes whose expression was altered in in tumors with the 1p/19q codeletion showed significant overlap with those involved in stemness and differentiation and genes that had CpG-rich promoters. Furthermore, there was an overlap with genes with altered expression in chronic myelogenous leukemia (CML). When we compared the expression of genes located on 1p and 19q between the tumors with the 1p/19q codeletion and those without, we found that only 82% of genes on 1p and 19q were downregulated significantly. When we ran the upregulated genes in PathScan, we found enrichment in GA binding protein alpha (GABPA)binding sites. GABPA expression levels were increased in our glioma samples with and without the 1p/19q codeletion. Investigating the expression levels of GABPA in the Cancer Genome Atlas (TCGA) GBM dataset also revealed an upregulation of this transcription factor. An increase in GABPA-mediated transcription was recently reported in CML but has not been yet reported in gliomas. We therefore propose that GABPA is an important transcription factor in gliomas. We are currently evaluating the function of GABPA in glioma what will also be presented.

Acknowledgements: This project was partially supported by a MeDDrive grant of the Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden.

Citation Format: Barbara Klink, Karol Szafranski, Jaime Campos-Valenzuela, Sophie Eisenreich, Dietmar Krex, Eva-Maria Gerlach, Karl Hackmann, Andreas Rump, Gabriele Schackert, Matthias Platzer, Lars Kaderali, Evelin Schröck, Khalil Abou-El-Ardat. Upregulation of gene expression in oligodendrogliomas is linked to an increase in GA binding protein alpha transcription. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3387. doi:10.1158/1538-7445.AM2014-3387