Abstract
Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH wt long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH wt cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup.
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Acknowledgments
We thank Steffen Dettling and Saskia Rösch for proofreading of the manuscript as well as Anja Metzner and Daniela Zito for review of patient data. Furthermore, we thank Farzaneh Kashfi, Hildegard Göltzer, Ilka Hearn and Melanie Greibich as well as Barbara Schwager and Claudia Rittmüller for their excellent technical assistance. This study has been funded in part by a grant from the Anni Hofmann Stiftung to CHM and the German Federal Ministry of Research and Education (BMBF) to BB (01GS0883).
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The authors declare that they have no conflict of interest.
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This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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C. Geisenberger, A. Mock, A. Abdollahi and C. Herold-Mende have contributed equally to this work.
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401_2015_1427_MOESM1_ESM.pdf
Fig. S1 TCGA subtypes in LTS/STS discovery cohort. Fig. S2 Principal Component Analysis of LTS and STS gene expression data. Fig. S3 Microglial infiltration in LTS and STS tumors. Fig. S4 Correlation of TCGA expression data and microglia signature. Fig. S5 Survival for combined „LTS-like“-status and chr. 19/20 co-gain. Fig. S6 Study cohort for chromosome 19/20 FISH validation (PDF 968 kb)
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Geisenberger, C., Mock, A., Warta, R. et al. Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain. Acta Neuropathol 130, 419–434 (2015). https://doi.org/10.1007/s00401-015-1427-y
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DOI: https://doi.org/10.1007/s00401-015-1427-y