Molecular Diagnostics of Gliomas

Department of Pathology, University of Pittsburgh, 200 Lothrop Ave, Pittsburgh, PA 15213, USA.
Archives of pathology & laboratory medicine (Impact Factor: 2.84). 05/2011; 135(5):558-68. DOI: 10.1043/2010-0649-RAIR.1
Source: PubMed


Gliomas are the most common primary brain tumors of adults and include a variety of histologic types and morphologies. Histologic evaluation remains the gold standard for glioma diagnosis; however, diagnostic difficulty may arise from tumor heterogeneity, overlapping morphologic features, and tumor sampling. Recently, our knowledge about the genetics of these tumors has expanded, and new molecular markers have been developed. Some of these markers have shown diagnostic value, whereas others are useful prognosticators for patient survival and therapeutic response.
To review the most clinically useful molecular markers and their detection techniques in gliomas.
Review of the pertinent literature and personal experience with the molecular testing in gliomas.
This article provides an overview of the most common molecular markers in neurooncology, including 1p/19q codeletion in oligodendroglial tumors, mutations in the isocitrate dehydrogenase 1 and 2 genes in diffuse gliomas, hypermethylation of the O(6)-methylguanine-DNA methyltransferase gene promoter in glioblastomas and anaplastic gliomas, alterations in the epidermal growth factor receptor and phosphatase and tensin homolog genes in high-grade gliomas, as well as BRAF alterations in pilocytic astrocytomas. Molecular testing of gliomas is increasingly used in routine clinical practice and requires that neuropathologists be familiar with these genetic markers and the molecular diagnostic techniques for their detection.

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    • "High-grade gliomas (HGG) are the most common primary tumors in the central nervous system (CNS) in adults [1]. Despite remarkable advances in cancer research and in neurosurgery, radiotherapy and chemotherapy, these patients still face a poor prognosis, pointing towards an urgent need for new therapeutic approaches [2]. "
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    ABSTRACT: The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. Trial registration Cuban National Register for clinical trials (No. 1745) (
    Full-text · Article · Jun 2013 · BMC Cancer
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    • "The incidence of primary brain tumors worldwide is approximately 7 out of 100,000 individuals per year, accounting for 2% of all primary tumors (Furnari et al., 2007). Gliomas are the most common primary brain tumors of adults and include a variety of histologic types and morphologies (Nikiforova and Hamilton, 2011). Glioblastoma (GBM) is the highest grade glioma variant, and is associated with high morbidity, mortality, and recurrence (median survival of 12–15 months) which recur even after extensive surgery and chemo-radiotherapy (Wen and Kesari, 2008). "
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    ABSTRACT: Patients with glioblastoma are commonly treated with chemotherapy. But a significant proportion of patients develop disease progression after an initial response to chemotherapy. Presently, there is no standard of care for such patients. The bone morphogenetic protein 4 (BMP4) has been reported to play tumor-suppressing role in glioblastoma, but its role in glioblastoma multidrug resistance (MDR) is not clear. We reported that BMP4 can reverse MDR of glioblastoma through the inhibition of B-cell lymphoma 2(BCL-2) and glial cell derived neurotrophic factor (GDNF). We showed that the expression level of BMP4 was lower in glioblastoma compared to normal brain tissue, and also showed that BMP4 expression decreased in multidrug resistance cell line U251/TMZ compared to U251 cells. Our research demonstrated that over expression of BMP4 can reverse the multidrug resistance. BCL-2 and GDNF were inhibited when BMP4 was over-expressed, and this data was consistent with the negative relationship in human samples, analysis of 40 patient's glioblastoma and brain samples revealed a significant negative correlation between BMP4 and BCL-2, GDNF. When BCL-2 and GDNF were knocked down, the effect of BMP4 in regulating MDR was partially lost. This novel result showed, for the first time, that BMP4 can reverse MDR in glioblastoma, which involved negative inhibition of BCL-2 and GDNF.
    Full-text · Article · Mar 2013 · Brain research
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    • "Similar results in terms of no statistical significance were obtained when considering the status of MGMT protein expression in the same subgroup of glioblastomas (P = 0.2309) (Additional File 2). Recent mutational analyses also revealed that somatic mutations in the NADP-dependent isocitrate dehydrogenase genes, IDH1 and IDH2, were associated with an increased overall survival of glioblastoma patients [27,32,33]. However, these mutations are rare in primary glioblastomas (grade IV)--the group of gliomas used in this work-- while are most frequent in tumors that evolved from lower-grade gliomas (secondary glioblastomas) [27,33]. "
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    ABSTRACT: RecQ helicases play an essential role in the maintenance of genome stability. In humans, loss of RecQ helicase function is linked with predisposition to cancer and/or premature ageing. Current data show that the specific depletion of the human RECQ1 helicase leads to mitotic catastrophe in cancer cells and inhibition of tumor growth in mice. Here, we show that RECQ1 is highly expressed in various types of solid tumors. However, only in the case of brain gliomas, the high expression of RECQ1 in glioblastoma tissues is paralleled by a lower expression in the control samples due to the poor expression of RECQ1 in non-dividing tissues. This conclusion is validated by immunohistochemical analysis of a tissue microarray containing 63 primary glioblastomas and 19 perilesional tissue samples, as control. We also show that acute depletion of RECQ1 by RNAi results in a significant reduction of cellular proliferation, perturbation of S-phase progression, and spontaneous γ-H2AX foci formation in T98G and U-87 glioblastoma cells. Moreover, RECQ1 depleted T98G and U-87 cells are hypersensitive to HU or temozolomide treatment. Collectively, these results indicate that RECQ1 has a unique and important role in the maintenance of genome integrity. Our results also suggest that RECQ1 might represent a new suitable target for anti cancer therapies aimed to arrest cell proliferation in brain gliomas.
    Full-text · Article · Jul 2011 · Molecular Cancer
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