An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data—gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information—are relatively scarce. We proposed an algorithm to build ‘association modules’ linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector–target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM—such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations—passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations—such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions—were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome 10 CNVs manifested strong negative and positive associations with survival times in brain tumors. By aligning the information of association modules with the established GBM subclasses based on transcription or methylation levels, we found each subclass possessed multiple concurrent molecular aberrations. Furthermore, the joint molecular characteristics derived from 16 association modules had prognostic power not explained away by the strong biomarker of CpG island methylator phenotypes. Functional and survival analyses indicated that immune/inflammatory responses and epithelial-mesenchymal transitions were among the most important determining processes of prognosis. Finally, we demonstrated that certain molecular aberrations uniquely recurred in GBM but were relatively rare in non-GBM glioma cells. These results justify the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM.

Mir-21–Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact

“…Class B tumors contained a preponderance of the proneural and classical signatures. The combined, contextdependent effects of high levels of Sox2, a stemness regulator (Shimozaki et al, 2012) and a marker of proneural GBM , and low levels of miR-21, a regulator of many oncogenic functions in several cancers (Sheedy, 2015) and a marker of mesenchymal tumors (Sintupisut et al, 2013), likely contributed to the unique properties of Class B tumors. The high Sox2 and low miR-21 levels also likely resulted in higher expression of EGFR, a marker of classical GBM tumors , in these tumors.…”

Targeting strategies on miRNA-21 and PDCD4 for glioblastoma

“…46,47 Studies have shown that inhibition of miR-21 increased glioblastoma cellular apoptosis, halted cell cycle in G1/S phase, and diminished tumor growth via inhibited epidermal growth factor receptor (EGFR) signaling pathway. 48,49 The latter regulates multiple cancer genes including PDCD4, 50 p53 signaling network, 51 It has been demonstrated that STAT3 directly activates miR-21, which promotes cancer cell survival and proliferation. 55,56 While some miRs directly regulate STAT3, there are findings demonstrating indirect STAT regulation by miRs also mediates important biological mechanisms.…”

Differential gene methylation in paired glioblastomas suggests a role of immune response pathways in tumor progression

“…More precisely, a recent study of paired breast cancer samples (before and after radiotherapy) showed that the most differently methylated pathways were linked to the immune system [44]. In the same line, the crosstalk between immune system and cancer progression has also been highlighted in glioblastoma by integrating multi-omic data showing that immune/inflammatory responses are among the most important processes associated with prognosis [45]. The association between GBM and infiltration of immune cells with poor survival has also been suggested in other studies [46,47].…”