Abstract 4928: Deregulation of asymmetry genes in oligodendrogliomas and glioblastomas

Abstract

Abstract BACKGROUND. Normal neural stem cells and NG2+ oligodendrocyte progenitors (OPC) undergo asymmetric cell division to generate a balanced number of self-renewing and differentiating progeny. Our recent studies showed that NG2+ OPC are the tumor-forming cells in oligodendrogliomas (ODG), a therapy-sensitive glioma. We provide cellular and molecular evidence that defects in asymmetric division of NG2+ OPC might contribute to tumor-initiation in oligodendrogliomas. In contrast, tumor-initiating cells in the highly resistant glioblastomas (GBM) express stem cell markers and show a high number of asymmetric divisions. We propose that distinct key asymmetry genes might be deregulated in the two types of tumor-initiating cells causing them to generate progeny with distinct therapy-sensitivity. Identifying these asymmetry key regulator networks will elucidate the mechanism by which tumor-initiating cells in gliomas maintain tumors and re-grow them after therapy. METHOD. A knowledge based network, consisting of asymmetry-genes and their transcriptional regulators, was constructed and refined by correlated gene expression. Subsequently, copy number and methylation were mapped onto the network and their impact on expression was assessed. In addition, the expression profiles of asymmetry genes within glioma samples were compared against their counterparts in normal brain samples and putative associations between expression and clinical outcome were tested. RESULTS. Our study has identified cancer- and differentiation associated transcription factors as putative regulators of asymmetry genes. In GBM tumors it was found that asymmetry genes are mostly affected by single copy gains and heterozygous deletions with an apparent influence on gene expression. When considered upon ODG tumors, the pattern of deregulation was distinct from that observed in GBM: for a subset of asymmetry genes a mutually exclusive deregulation was observable in either GBM or ODG, while another gene subset was progressively deregulated in ODG- and GBM. Taken together, our results indicate that asymmetry genes are distinctly regulated in ODG and GBM. We will discuss a model how this could contribute to distinct levels of therapy resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4928. doi:1538-7445.AM2012-4928