Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

Christoph Geisenberger, Andreas Mock, Rolf Warta, Carmen Rapp, Christian Schwager, Andrey Korshunov, Ann Katrin Nied, David Capper, Benedikt Brors, Christine Jungk, David Jones, V. Peter Collins, Koichi Ichimura, L. Magnus Bäcklund, Elena Schnabel, Michel Mittelbron, Bernd Lahrmann, Siyuan Zheng, Roel G.W. Verhaak, Niels GrabeStefan M. Pfister, Christian Hartmann, Andreas von Deimling, Jürgen Debus, Andreas Unterberg, Amir Abdollahi, Christel Herold-Mende

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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, IDHwt 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, IDHwt 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.

Original languageEnglish (US)
Pages (from-to)419-434
Number of pages16
JournalActa Neuropathologica
Volume130
Issue number3
DOIs
StatePublished - Sep 21 2015
Externally publishedYes

Keywords

  • Glioblastoma
  • Long-term survival
  • Microglia
  • Molecular profiling
  • Short-term survival

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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