title: Comparative transcriptomics reveals similarities and differences between astrocytoma grades.
abstract: BACKGROUND
  Astrocytomas are the most common primary brain tumors distinguished into four histological grades. Molecular analyses of individual astrocytoma grades have revealed detailed insights into genetic, transcriptomic and epigenetic alterations. This provides an excellent basis to identify similarities and differences between astrocytoma grades.
  
  
  METHODS
  We utilized public omics data of all four astrocytoma grades focusing on pilocytic astrocytomas (PA I), diffuse astrocytomas (AS II), anaplastic astrocytomas (AS III) and glioblastomas (GBM IV) to identify similarities and differences using well-established bioinformatics and systems biology approaches. We further validated the expression and localization of Ang2 involved in angiogenesis using immunohistochemistry.
  
  
  RESULTS
  Our analyses show similarities and differences between astrocytoma grades at the level of individual genes, signaling pathways and regulatory networks. We identified many differentially expressed genes that were either exclusively observed in a specific astrocytoma grade or commonly affected in specific subsets of astrocytoma grades in comparison to normal brain. Further, the number of differentially expressed genes generally increased with the astrocytoma grade with one major exception. The cytokine receptor pathway showed nearly the same number of differentially expressed genes in PA I and GBM IV and was further characterized by a significant overlap of commonly altered genes and an exclusive enrichment of overexpressed cancer genes in GBM IV. Additional analyses revealed a strong exclusive overexpression of CX3CL1 (fractalkine) and its receptor CX3CR1 in PA I possibly contributing to the absence of invasive growth. We further found that PA I was significantly associated with the mesenchymal subtype typically observed for very aggressive GBM IV. Expression of endothelial and mesenchymal markers (ANGPT2, CHI3L1) indicated a stronger contribution of the micro-environment to the manifestation of the mesenchymal subtype than the tumor biology itself. We further inferred a transcriptional regulatory network associated with specific expression differences distinguishing PA I from AS II, AS III and GBM IV. Major central transcriptional regulators were involved in brain development, cell cycle control, proliferation, apoptosis, chromatin remodeling or DNA methylation. Many of these regulators showed directly underlying DNA methylation changes in PA I or gene copy number mutations in AS II, AS III and GBM IV.
  
  
  CONCLUSIONS
  This computational study characterizes similarities and differences between all four astrocytoma grades confirming known and revealing novel insights into astrocytoma biology. Our findings represent a valuable resource for future computational and experimental studies.
authors.affiliation: Innovative Methods of Computing, Center for Information Services and High Performance Computing, Dresden University of Technology, Dresden, Germany. michael.seifert@tu-dresden.de.|Cellular Networks and Systems Biology, University of Cologne, CECAD, Cologne, Germany. michael.seifert@tu-dresden.de.|Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. michael.seifert@tu-dresden.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Innovative Methods of Computing, Center for Information Services and High Performance Computing, Dresden University of Technology, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Garbe
authors.affiliation: Innovative Methods of Computing, Center for Information Services and High Performance Computing, Dresden University of Technology, Dresden, Germany.|Institute of Molecular Systems Biology, Zurich, Switzerland.
authors.forename: Betty
authors.initials: B
authors.lastname: Friedrich
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
mesh_terms: D001254:Astrocytoma / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D059467:Transcriptome