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

• Published in: Acta neuropathologica Vol. 130; no. 3; pp. 419 - 434
• Main Authors: Geisenberger, Christoph, Mock, Andreas, Warta, Rolf, Rapp, Carmen, Schwager, Christian, Korshunov, Andrey, Nied, Ann-Katrin, Capper, David, Brors, Benedikt, Jungk, Christine, Jones, David, Collins, V. Peter, Ichimura, Koichi, Bäcklund, L. Magnus, Schnabel, Elena, Mittelbron, Michel, Lahrmann, Bernd, Zheng, Siyuan, Verhaak, Roel G. W., Grabe, Niels, Pfister, Stefan M., Hartmann, Christian, von Deimling, Andreas, Debus, Jürgen, Unterberg, Andreas, Abdollahi, Amir, Herold-Mende, Christel
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2015; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Brain - metabolism; Brain - pathology; Brain - surgery; Brain cancer; Brain Neoplasms - diagnosis; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer research; Chromosomes; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 20; Cohort Studies; Consortia; DNA methylation; Enzymes; Female; Gene expression; Genomes; Glioblastoma - diagnosis; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastomas; Hospitals; Humans; Isocitrate Dehydrogenase - genetics; Macrophages - metabolism; Macrophages - pathology; Male; Medical research; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Microglia - metabolism; Microglia - pathology; Middle Aged; Mutation; Neuropathology; Neurosciences; Neurosurgery; Oncology; Original Paper; Pathology; Prognosis; Radiation; Research centers; RNA; RNA, Messenger - metabolism; Survival Analysis; Survivors; Time Factors; Transcription, Genetic; Tumors; Germany; Long-term survival; Molecular profiling; Short-term survival; Glioblastoma; Microglia
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-015-1427-y

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.