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

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.

Multidimensional scaling of diffuse gliomas: application to the 2016 World Health Organization classification system with prognostically relevant molecular subtype discovery

“…Furthermore, subgroups B and C can be simply distinguished by chromosome 19 gain. Co-gain of chromosomes 19 and 20, which has been described in a small series of long-term glioblastoma survivors [14], is frequently observed in the IDH-wildtype subgroup B. There is a significant survival difference ( p = 0.034 , Cox proportional hazards regression) between subgroups B and C, which are distinguished by gain of chromosome 19 (Additional file 1: Figure S1).…”

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

“…However, the reduced frequency of total/near total resections in telomerase with macrophages tumors may be a contributing factor to a poorer response to temozolomide. According to Geisenberger et al, 59 long-term survivors had an M1 macrophage compared with short-term survivors that had an M2 macrophage gene signature. 59 In additional to an altered immune signature, the same study found that long-term survivors were distinguished by a concurrent gain of chromosomes 19 and 20.…”

“…According to Geisenberger et al, 59 long-term survivors had an M1 macrophage compared with short-term survivors that had an M2 macrophage gene signature. 59 In additional to an altered immune signature, the same study found that long-term survivors were distinguished by a concurrent gain of chromosomes 19 and 20. 59 Targeting M2 macrophages by removing them or switching them to a proinflammatory phenotype are potential new strategies for treatment.…”

Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma

“…Classic genetic markers of favorable prognosis such as O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation or isocitrate dehydrogenase (IDH) mutation do not fully account for LTS-GBM (Hartmann et al 2013;Gerber et al 2014;Amelot et al 2015;Millward et al 2016;Sarmiento et al 2016;Smrdel et al 2016). Review of the literature reveals a report of concurrent gain of chromosomes 19 and 20 as a favorable prognostic factor for a subset of LTS-GBM that did not show IDH mutation-related DNA methylation pattern called 'Glioma CpG Island Hypermethylator Phenotype (G-CIMP)' (Geisenberger et al 2015). However, multiple studies revealed no distinctive DNA copy number changes in LTS-GBM (Hartmann et al 2013;Gerber et al 2014;Reifenberger et al 2014).…”