Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial (original) (raw)
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A Simplified Approach for the Molecular Classification of Glioblastomas
PLoS ONE, 2012
Glioblastoma (GBM) is the most common malignant primary brain tumors in adults and exhibit striking aggressiveness. Although GBM constitute a single histological entity, they exhibit considerable variability in biological behavior, resulting in significant differences in terms of prognosis and response to treatment. In an attempt to better understand the biology of GBM, many groups have performed high-scale profiling studies based on gene or protein expression. These studies have revealed the existence of several GBM subtypes. Although there remains to be a clear consensus, two to four major subtypes have been identified. Interestingly, these different subtypes are associated with both differential prognoses and responses to therapy. In the present study, we investigated an alternative immunohistochemistry (IHC)-based approach to achieve a molecular classification for GBM. For this purpose, a cohort of 100 surgical GBM samples was retrospectively evaluated by immunohistochemical analysis of EGFR, PDGFRA and p53. The quantitative analysis of these immunostainings allowed us to identify the following two GBM subtypes: the ''Classical-like'' (CL) subtype, characterized by EGFR-positive and p53-and PDGFRA-negative staining and the ''Proneural-like'' (PNL) subtype, characterized by p53-and/or PDGFRA-positive staining. This classification represents an independent prognostic factor in terms of overall survival compared to age, extent of resection and adjuvant treatment, with a significantly longer survival associated with the PNL subtype. Moreover, these two GBM subtypes exhibited different responses to chemotherapy. The addition of temozolomide to conventional radiotherapy significantly improved the survival of patients belonging to the CL subtype, but it did not affect the survival of patients belonging to the PNL subtype. We have thus shown that it is possible to differentiate between different clinically relevant subtypes of GBM by using IHC-based profiling, a method that is advantageous in its ease of daily implementation and in large-scale clinical application.
Cellular Oncology, 2011
Background: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO). Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data. Methods: The oligodendroglial and the "classic" glioblastoma parts of 13 GBMO were analyzed separately by interphase fluorescence in situ hybridization (FISH) on paraffin sections using a custom probe set (regions 1p, 1q, 7q, 10q, 17p, 19q, cen18, 21q) and by comparative genomic hybridization (CGH) of microdissected paraffin embedded tumor tissue. Results: We identified four distinct genetic subtypes in 13 GBMOs: an "astrocytic" subtype (9/13) characterized by +7/−10; an "oligodendroglial" subtype with −1p/−19q (1/13); an "intermediate" subtype showing +7/−1p (1/13), and an "other" subtype having none of the former aberrations typical for gliomas (2/13). The different histological tumor parts of GBMO revealed common genetic changes in all tumors and showed additional aberrations specific for each part. Conclusion: Our findings demonstrate the monoclonal origin of GBMO followed by the development of the astrocytic and oligodendroglial components. The diagnostic determination of the genetic signatures may allow for a better prognostication of the patients.
PLoS ONE, 2010
The Cancer Genome Atlas Project (TCGA) has produced an extensive collection of '-omic' data on glioblastoma (GBM), resulting in several key insights on expression signatures. Despite the richness of TCGA GBM data, the absence of lower grade gliomas in this data set prevents analysis genes related to progression and the uncovering of predictive signatures. A complementary dataset exists in the form of the NCI Repository for Molecular Brain Neoplasia Data (Rembrandt), which contains molecular and clinical data for diffuse gliomas across the full spectrum of histologic class and grade. Here we present an investigation of the significance of the TCGA consortium's expression classification when applied to Rembrandt gliomas. We demonstrate that the proneural signature predicts improved clinical outcome among 176 Rembrandt gliomas that includes all histologies and grades, including GBMs (log rank test p = 1.16e-6), but also among 75 grade II and grade III samples (p = 2.65e-4). This gene expression signature was enriched in tumors with oligodendroglioma histology and also predicted improved survival in this tumor type (n = 43, p = 1.25e-4). Thus, expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for lower grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy. Integrated DNA and RNA analysis of low-grade and high-grade proneural gliomas identified increased expression and gene amplification of several genes including GLIS3, TGFB2, TNC, AURKA, and VEGFA in proneural GBMs, with corresponding loss of DLL3 and HEY2. Pathway analysis highlights the importance of the Notch and Hedgehog pathways in the proneural subtype. This demonstrates that the expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for low-grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy.
Neuro-Oncology, 2013
Background. Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification-however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation. Methods. We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome. Results. GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P ¼ .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P ¼ .005). Singular LOH of 19q (P ¼ .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P ¼ .8, P ¼ 1.0, P ¼ 1.0, respectively). Conclusions. Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM.
A clinicopathological and molecular analysis of glioblastoma multiforme with long-term survival
Journal of Clinical …, 2011
The median survival time of patients with glioblastoma multiforme (GBM) is 12 months, and only 3-5% of patients survive longer than 3 years. We performed histomorphological and detailed molecular analyses of seven long-term survivors of GBM to identify any prognostic factors that potentially contribute to survival. Morphology and immunohistochemistry for p53, phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) protein expression were investigated. EGFR amplification and 1p/19q deletion were assessed by fluorescent in situ hybridization. The O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status was evaluated by performing methylation-specific polymerase chain reaction assays. All tumors were classical GBMs and no significant oligodendroglial differentiation was noted. The majority showed EGFR amplification (4/7), PTEN protein expression (6/7) and MGMT promoter methylation (5/6). Immunopositivity for p53 was noted in three of seven patients. Deletion of chromosome 1p/19q, either isolated or combined, was not identified in any of the se patients. All patients were treated by gross total resection followed by radiotherapy; six patients received additional temozolomide treatment. A relatively young age of onset (48 years), with a high MGMT promoter methylation and PTEN protein expression were favorable factors for long-term survival. The presence of EGFR amplification indicates that more than a single factor determines survival in GBM.
The median survival time of patients with glioblastoma multiforme (GBM) is 12 months, and only 3–5% of patients survive longer than 3 years. We performed histomorphological and detailed molecular analyses of seven long-term survivors of GBM to identify any prognostic factors that potentially contribute to survival. Morphology and immunohistochemistry for p53, phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) protein expression were investigated. EGFR amplification and 1p/19q deletion were assessed by fluorescent in situ hybridization. The O6-methylguanine–DNA methyltransferase (MGMT) gene methylation status was evaluated by performing methylation-specific polymerase chain reaction assays. All tumors were classical GBMs and no significant oligodendroglial differentiation was noted. The majority showed EGFR amplification (4/7), PTEN protein expression (6/7) and MGMT promoter methylation (5/6). Immunopositivity for p53 was noted in three of seven patients. Deletion of chromosome 1p/19q, either isolated or combined, was not identified in any of the se patients. All patients were treated by gross total resection followed by radiotherapy; six patients received additional temozolomide treatment. A relatively young age of onset (48 years), with a high MGMT promoter meth-ylation and PTEN protein expression were favorable factors for long-term survival. The presence of EGFR amplification indicates that more than a single factor determines survival in GBM.
Biomedical Journal of Scientific & Technical Research, 2018
Glioblastoma (GBM-GIV astrocytoma) represents the most noted neoplasms of the brain usually reported with dismal prognosis. The term glioblastoma with oligodendroglial component (GBMO) represents the present of oligodendroglial foci in glioblastoma tumors. GBMOs are usually represented with better therapeutic response and concomitant prognostic outcome. We have observed nearly 610 cases of various pathologic grades of astrocytoma from 2009 to 2014 and found the oligodendroglial component among the 40 cases. Nearly in all the cases of GBM and GBMOs received complete resection and was followed by standard therapeutic regime of radiotherapy and chemotherapy with temozolomide. The survival pattern was observed in patients diagnosed with GBM and GBMO. We have looked for the presence of MIB1, p53 and necrosis pattern in selected GBMO sub group. We observe nearly 54% of GBMOs stained positive with p53. Necrosis and MIB1 was observed in most of the GBMO cases. These was statistically significant difference among survival of glioblastoma patients' and GBMOs. Glioblastoma multiformae patients with oligodendroglial component was observed to have median survival of 16 months while with GBM it was observed to be 12 months. GBMO were found to have significantly longer survival than glioblastoma patients' and respond well to chemo and radiotherapy.
Cerebral glioblastoma with oligodendrogliomal component: analysis of 36 cases
Journal of neuro- …, 2009
Not all Glioblastoma multiforme (GBM, grade IV WHO) manifest the same clinical course. Different prognostic classes may arise from different morphologic and genetic profiles. The observation of oligodendroglial foci within GBM samples and their correlation with genetic alterations may predict a better prognosis. 450 patients affected by histologically proven supratentorial cerebral GBM were treated at our institutions from January 2000 to December 2006: all patients received at least subtotal surgical removal, followed by the same standard radiochemotherapy adjuvant treatment. In a subgroup of 36 patients (8.0%) an oligodendroglial component was observed. Molecular assessment of these cases was performed and LOH for 1p, 19q and 10q, EGFR amplification and TP53 gene expression was determined. Median age of this subgroup was 52.1 years (range: 29-78 years) vs 62.4 years in the entire GBM population. Chromosome analysis resulted as follows: LOH 1p and/or 19q in 27 cases (75.0%), LOH of 10q in 21 cases (58.1%), EGFR amplification in 14 cases (39%) and TP53 mutation in eight patients (22.2%). OS was of 20.9 months while it was 13.6 months in the entire GBM population. Progression free survival (PFS) was 10.3 months and 7.6 months the entire group. Two-year survival was of 55%. The presence of an oligodendroglial component in GBM appears to be an important prognostic factor to which better prognosis can be related. LOH 1p and 19q was significantly associated with GBM with oligodendroglial component.
Cancer Investigation, 2009
To understand the pathogenesis of glioblastoma multiforme (GBM) we used high-resolution comparative genomic hybridization arrays and gene expression microarrays to identify DNA copy number alterations and gene expression changes in comparable sets of GBM samples. Gains were detected at chromosomes 1, 2, 7, 9, 12, 19, and 20 and losses at 6, 9, and 10. Gene expression analyses identified specific genes overexpressed in GBM mapping at amplified chromosomal regions. Among these genes we found genes involved in angiogenesis, extracellular matrix remodeling and several oncogenes. DNA copy number analysis along with gene expression profiles provides a powerful strategy to understand tumor progression and identification of genes involved in GBM pathogenesis. 541 Cancer Invest Downloaded from informahealthcare.com by HINARI on 11/21/12