Glioma

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The newly released World Health Organization Classification of Tumors of the Central Nervous System 2016 has implemented molecular information in the classification of brain tumors. A number of large-scale retrospective studies have indicated that molecular data are of diagnostic and prognostic relevance in neuro-oncology. Incorporation of molecular studies has become a prerequisite in standard-of-care practice of neuro-oncology. Next-generation sequencing (NGS) or massively parallel sequencing allows simultaneously sequencing millions of DNA fragments in an acceptable period. The technique allows examination of a number of genes and gene regions simultaneously and is capable of detecting a wide variety of molecular alterations. NGS has been rapidly adopted in cancer studies to identify mutational landscape, copy number variation, novel fusion genes, and others. With its rapidly declining cost, NGS is slowly replacing conventional molecular techniques in cancer diagnosis. In this review, we will review the development of NGS and common sequencing strategies in oncology laboratories. We will then discuss the application of NGS in detecting genetic aberrations in neuro-oncology.

Background: Molecular markers including isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion have been incorporated into the World Health Organization (WHO) 2016 classification of diffuse gliomas for integrated diagnostic reporting. The prognostic relevance of BRAF mutation among the newly established molecularly defined entities of gliomas remained relatively unexplored. Materials and Methods: We examined BRAF mutation in 578 adult diffuse gliomas and examined the clinical significance of the mutation in five histomolecular subgroups, namely oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (Group I), astrocytomas, IDH- mutant (Group II), astrocytomas, IDH-wild-type (Group III), glioblastoma, IDH-mutant (Group IV), and glioblastoma, IDH-wild type (Group V). Results: Mutation rate of BRAF was 5.9% across the whole cohort and was 4.9%, 7.5%, and 7.0% in Group II, Group III, and Group V gliomas, respectively. Univariate analysis revealed a trend of poor overall survival in BRAF-mutant tumors among Group II gliomas, a trend which was also demonstrated by multivariable analysis. Among Group III and Group V gliomas, BRAF-mutant tumors seemed to exhibit more favorable survival in univariate analysis. Multivariable analysis further demonstrated the favorable prognostic significance of BRAF mutation in Group III (hazard ratio [HR] = 0.31, 95% confidence interval [CI] = 0.10–0.95, P = 0.04) and Group V gliomas (HR = 0.44, 95% CI = 0.18–1.09, P = 0.077). Conclusion: BRAF mutation appears to mark out a small subset of adult infiltrative gliomas with the distinct clinical outcome. Mutational analysis of BRAF can potentially contribute to the clinical risk stratification in the management of glioma patients in the context of the WHO 2016 classification.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median survival rate of GBM patients is approximately 14 months and tumor recurrence is almost inevitable. With the increased use of immunotherapy, immune response and edema found on posttreatment magnetic resonance imaging (MRI) may be misinterpreted as tumor progression. Distinguishing the true radiographic progression from pseudo-progression by MRI is often difficult. Peripheral biomarkers are needed to identify the true tumor recurrence and evaluate therapy response. Exosomes isolated from both blood and cerebrospinal fluid are cargo containers utilized by eukaryotic cells to exchange biomolecules such as proteins, mRNA, and microRNA (miRNA). These biomolecules participate in cell-cell communication, cell migration, angiogenesis, and tumor growth. Isolation of RNA (including miRNA) from exosomes can yield a greater concentration compared with circulating mRNA directly taken from body fluid as molecules within exosomes are not degraded by nucleases and proteases. Not only are exosomes a novel approach to biomarker detection, but they may also provide potential therapeutic interventional targets. In addition, exosomes are critical in miRNA replacement therapy as they can act as a carrier for anticancer drug delivery. This review focuses on the advances in basic research of exosome-related potential biomarkers and discusses their potential application in the diagnosis, prognosis, and treatment of GBM.

Background: The alkylating agent temozolomide (TMZ) is widely used in glioblastoma multiforme (GBM) therapy. Unfortunately, TMZ-resistance frequently occurs in recurrent GBM and is the major cause of treatment failure. The anti-malarial drug quinacrine (QC) harbors antitumor and chemosensitivity properties, but its interactions with TMZ in GBM remain unclear. This study aimed to investigate whether QC would sensitize TMZ in TMZ-sensitive and TMZ-resistant GBM cells as well as the underlying mechanisms. Materials and Methods: The cytotoxicity of QC and TMZ in TMZ-sensitive and TMZ-resistant GBM cells was evaluated using in vitro cell viability assay and colony formation assay. Cellular apoptosis and protein expression levels were determined using TUNEL assay and immunoblotting, respectively. Results: QC substantially enhanced TMZ cytotoxicity in both TMZ-sensitive and TMZ-resistant cells. Such cytotoxic effect was accompanied by changes in the expression levels of LC3II, p62 and cleaved caspase 3, and increased cellular apoptosis. The results suggested that QC could sensitize GBM cells to TMZ at least partially through apoptosis induction, in which autophagy inhibition might be involved. Conclusion: The antimalarial drug QC may hold promise as a potentiation of TMZ treatment in GBM, especially in cases of TMZ-resistance.

Malignant glioma is the most common primary brain tumor. Over the past four decades, intensive researches and studies have made breakthroughs in survival. However, the overall prognosis is still very poor with short survival. Glioblastoma was one of the first selected tumors for the Cancer Genome Atlas project which had gained understanding in tumor biology and gliomagenesis. Despite all these understandings, targeted therapies and precision therapeutics have not made any impact in the overall survival and outcomes. The concept of precision personalized cancer therapy is appealing and is desperately needed to be materialized for glioma. The issues of tumor heterogeneity in glioma and drug screening are crucial to our further understanding and to the ultimate solution. This article will discuss the potential and challenges of precision cancer therapeutics for glioma.

Online since 6^th Sep 2017.