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Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC 50 ) values varied significantly (10 nM < IC 50 < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC 50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.

Background & Aims: Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI., Methods: CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG)., Results: At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%-95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%-85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%-96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%-96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%-79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%-100%; specificity, 100%)., Conclusions: In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis -predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10 -6 , we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10 -6 ). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus ( GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop., (©2019 American Association for Cancer Research.)

Introduction : Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 have been reported in a limited number of tumors. In gliomas, IDH mutations are primarily detected in WHO grade II-III tumors and represent a major biomarker with diagnostic, prognostic, and predictive implications. The recent development of IDH inhibitors and vaccines suggests that the IDH mutation is also an appealing target for therapy. Areas covered : This review focuses on the role of IDH mutations in diffuse gliomas. Besides discussing their role in gliomagenesis, we will emphasize the role of IDH mutations in clinical practice as a diagnostic, prognostic and predictive biomarker, and as a potential therapeutic target. Noninvasive detection of the IDH mutation by means of liquid biopsy and MR spectroscopy will also be discussed. Expert commentary : While IDH mutation is a consolidated diagnostic and prognostic biomarker in clinical practice, its role in oncogenesis is far from being elucidated, and there are several pending issues. The routine use of noninvasive techniques for detection and monitoring of the IDH status remains challenging. Although the IDH mutation is a very early alteration in gliomagenesis, it may then be omitted during tumor progression. This observation has important implications when designing targeted clinical trials.

Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affect 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG) and to compare performance of these methods with DNA sequencing and tissue 2HG analysis., Methods: Twenty-four subjects with suspected diagnosis of low-grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3T using 2 MRS methods, edited MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by a combination of automated immunohistochemical analysis and Sanger sequencing. Levels of 2HG in tissue samples measured by gas chromatography-mass spectrometry were compared with those estimated by MRS., Results: Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings., Conclusions: Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.

Background: Pyrosequencing is recognized as a strong technique to analyze the MGMT status of glioblastoma patients. The most commonly used assay, quantifies the methylation levels of CpGs 74 to 78. A more recent CE-marked In Vitro Diagnostic Medical Device (CE-IVD) assay, Therascreen, analyzes CpGs 76-79., Methods: We performed a comparison of these two assays to evaluate the potential impact of this shift in analyzed CpGs. Therascreen analysis was centrally performed for 102 glioblastoma patients, who were part of a prospective multicenter trial., Results: A strong correlation was observed for the mean values of the 4 or 5 analyzed CpGs, with lower values recorded using the Therascreen assay, especially for values greater than 20%. When considering a classification in 3 categories (> 12%: methylated; ⩽ 8%: unmethylated; 9-12%: grey zone), 93% of patients were identically classified between the two assays. Using a binary classification, 95% and 97% of patients were identically classified with cut-offs of 8% and 12%, respectively. A strong prognostic significance was observed for both assays: median overall survival were 15.9 months and 34.9 months for respectively unmethylated and methylated patients with either test., Conclusion: The results demonstrate that these assays may be used interchangeably.

Background: Meningiomas are the most common primary intracranial tumors in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the hope for targeted therapies. It would be useful to know the precise frequency of these mutations in anatomical subgroups and clarify their prognostic value., Methods: We used the Sanger sequencing technique to characterize 79 samples of olfactory groove meningiomas for SMO (L412F and W535L) and AKT1E17K mutations. We reviewed clinical data to assess the prognostic value of these mutations in this anatomical subgroup., Results: Out of the 79 patients with olfactory groove meningiomas, we identified targetable mutations in 34 patients (43%) (22 patients [28%] with SMO mutation-L412F almost exclusively-and 12 patients [15%] with AKT1 mutation). Meningiomas in the SMO-mutant group had an overall 36% recurrence rate, significantly higher than in the AKT1-mutant group (16%) and in the "SMO and AKT1 wildtype" group (11%) (χ2 test, P = .04). All late recurrences (after 5 y) occurred in the SMO-mutant group. Among grade I meningiomas, the SMO-mutant group was identified as having a significantly poorer prognosis. World Health Organization histological grade II (P = .006) and incomplete resection (P = .001) were independently associated with shorter recurrence-free survival., Conclusion: Molecular diagnosis of SMOL412F/W535L and AKT1E17K mutations improves prognostic evaluation in olfactory groove meningiomas and opens new therapeutic perspectives with SMO or AKT inhibitors for recurrent cases., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTex project (GBM and Experimental Therapeutics) a GBM patient-derived cell line (GBM-PDCL) library. A multi-omic approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors., Methods: Single nucleotide polymorphism array, expression arrays, exome sequencing, and RNA sequencing were used to measure and compare the molecular landscapes of 20 samples representing 10 human GBM tumors and paired GBM-PDCLs., Results: Copy number variations were similar for a median of 85% of the genome and for 59% of the major focal events. Somatic point mutations were similar in a median of 41%. Mutations in GBM driver and "druggable" genes were maintained in 67% of events. Mutations that were not conserved in the PDCL were mainly low allelic fraction and/or non-driver mutations. Based on RNA expression profiling, PDCLs cluster closely to their parental tumor with overexpression of pathways associated with cancer progression in PDCL., Conclusions: Overall, PDCLs recapitulate pivotal molecular alterations of paired-parental tumors supporting their use as a preclinical model of GBM. However, some driver aberrations are lost or gained in the passage from tumor to PDCL. Our results support using PDCL as a relevant preclinical model of GBM. Further investigations of changes between PDCLs and their parental tumor may provide insights into GBM biology., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status.

Background: Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile., Methods: Plasma samples from 111 patients with GBM and a subset of 40 patients with nonglial brain tumors were obtained preoperatively. Plasma from 99 healthy controls was also analyzed. IGFBP-2, YKL-40, and GFAP levels were determined using enzyme-linked immunoadsorbent assay tests. Their association with histological and radiological variables was assessed., Results: Circulating levels of all 3 proteins were found to be significantly higher in patients with GBM compared with healthy controls (P < .01). Only YKL-40 and GFAP were found to demonstrate significant differences between patients with GBM and nonglial brain tumors (P = .04). GFAP was undetectable (<0.02 ng/mL) in all patients without GBM. A receiver operating characteristic analysis accounting for a 2-step diagnostic procedure including the 3 biomarkers afforded an area under the curve of 0.77 for differentiating patients with GBM from those with nonglial brain tumors. There was a significant correlation between tumor volume and plasma IGFBP-2 level (Spearman Rho correlation coefficient, 0.22; P = .025) and GFAP (Spearman Rho correlation coefficient, 0.36; P < .001) among patients with GBM. Preoperative plasma IGFBP-2 levels were found to be independently associated with worse overall survival among patients with GBM (hazard ratio, 1.3; P = .05)., Conclusions: A combined profile of preoperative IGFBP-2, GFAP, and YKL-40 plasma levels could serve as an additional diagnostic tool for patients with inoperable brain lesions suggestive of GBM. In addition, IGFBP-2 levels appear to constitute an independent prognostic factor in patients with GBM., (© 2014 American Cancer Society.)

Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is heterogeneous across patients. Interestingly, predictive biomarkers of response to these classic chemotherapeutic agents have been identified in neuro-oncology (i.e., 1p/19q co-deletion, IDH mutation and O6-methylguanine DNA-methyltransferase promoter methylation). The most emblematic biomarker in glioblastoma is O6-methylguanine DNA-methyltransferase promoter methylation that predicts response to temozolomide. In parallel, innovative drugs are emerging. Some of these agents have shown some activity but in a limited number of glioblastoma patients. One of the major challenges is to identify molecular predictors of response to these smart drugs for an efficient personalized medicine. These novel agents have been tested in clinical trials enrolling glioblastoma patients. Although none of them has been validated prospectively in Phase III clinical trials, interesting molecular predictors of response to these drugs have been investigated and are presented in this review, which also reports more advanced biomarkers.

Background: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1)., Materials and Methods: We studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion., Results: rs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P = .01), 10q loss (P = .02); rs4295627 and 1p-19q codeletion (P = .04), rs498872 and IDH (P = .02), 9p loss (P = .04), and 10q loss (P = .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P < 10(-3)) and rs2736100 and rs6010620 with IDH wild-type gliomas (P < 10(-3) and P = .03)., Conclusion: The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.

Primary CNS tumors (PCNSTs) encompass a broad and heterogeneous group of tumors, including gliomas, meningiomas, embryonal tumors, primary CNS lymphomas, CNS germ cell tumors and sellar region tumors. In recent decades, research has focused on understanding the clinical and biological significance of molecular abnormalities detected in PCNSTs. The emergence of genomic arrays, including comparative genomic hybridization and SNP arrays, have helped in the discovery of novel critically important genes and novel genomic biomarkers involved in PCNST oncogenesis (e.g., BRAF duplication in pilocytic astrocytoma). Since a summary of data from genomic arrays using gliomas has been described in a previous review, in this article we will focus on the insights provided by genome-wide DNA arrays in the genetics and genomics of nonglial PCNSTs in adults. The high-throughput assessment of gene copy-number abnormalities has improved our knowledge of molecular pathogenesis in nonglial PCNSTs, allowing for the identification of new candidate genomic regions and genes involved in tumorigenesis. These chromosome imbalances provide a promising insight into potential targets for innovative drugs and new interesting diagnostic and prognostic biomarkers for clinical practice.

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed-validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs.

The neuronal intermediate filament alpha internexin (INA) is expressed in most gliomas with 1p19q codeletion and could represent a valuable prognostic marker in clinical routine. INA expression was analysed on 409 gliomas and correlated with histology, progression free survival (PFS), overall survival (OS), genomic profile assessed by CGH-array, IDH1/IDH2 mutation and p53 expression. INA was expressed in 59% of grade II oligodendrogliomas (n=73), 45% of grade III oligodendrogliomas (n=133), 15% of grade II oligoastrocytomas (n=61), 12% of grade III oligoastrocytomas (n=41), 23% of glioblastomas with oligodendroglial component (n=31), 0% of grade I astrocytomas (n=3), 0% of grade II astrocytomas (n=14), 6% of grade III astrocytomas (n=17) and 0% of glioblastomas (n=36). INA expression was detected in 85% of gliomas with complete 1p19q codeletion ('true 1p19q signature') (n=85) versus 15% of gliomas without 1p19q codeletion (n=245), including 14% of gliomas with variable/partial 1p19q deletion ('false 1p19q signature') (n=72) (p<0.0001). INA was expressed by 43% of gliomas with IDH1 mutation (n=197) versus 12% of gliomas without IDH1 mutation (n=156) (p<0.0001). In oligodendroglial gliomas (n=240), INA expression specificity for 1p19q codeletion was 80%, sensitivity 85%, positive predictive value 70%, and negative predictive value was 91%. Combining INA and p53 expressions improved INA predictive accuracy for 1p19q codeletion. In grade III gliomas, INA expression was associated with longer PFS (42.1 versus 10.2 months, p=0.0007) and longer OS (124.6 versus 20.6 months, p=0.0001). In conclusion, INA expression is a fast, cheap and reliable prognostic marker, and represents a surrogate marker for 1p19q complete codeletion., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In recent years, extensive molecular studies have identified diagnostic and prognostic markers in gliomas that reinforce the WHO histological classification. 1p19q codeletion, O(6)-methylguanine DNA methyltransferase (MGMT) status, and mutations of isocitrate dehydrogenases 1 and 2 (IDH1/IDH2) are currently the three most pertinent markers in diffuse gliomas. Ongoing clinical trials already stratify or select patients according to their 1p19q codeletion or MGMT status. Mutations of IDH1 have been recently identified as a major prognostic factor in diffuse gliomas. Future studies should determine whether IDH1/IDH2 mutations are predictive of response to treatments. Routine use of these markers considerably contributes to a more objective classification of gliomas based on both histological and molecular features.

Purpose: Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas., Patients and Methods: IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome., Results: A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10(-15)). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10(-14)) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10(-15)) and loss of chromosome 10 (P < 10(-15)). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021)., Conclusion: This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.

The MDM2 SNP309 variant has been shown to increase MDM2 expression and to be associated with tumor formation. In glioblastomas, the P53/MDM2 pathway is of crucial importance and MDM2 amplification is related to poor prognosis. However, we show here that MDM2 SNP309 is not associated with glioblastoma risk, and is not a prognostic factor.

FABP7 expression has been analysed in a series of 123 glioblastomas (68 pure GBM, 55 GBMO, i.e. with oligodendroglial component). FABP7, found in 91/123 samples, showed a pure cytoplasmic expression in 69 cases, and cytoplasmic+nuclear expression in 22 cases. FABP7 expression was associated with pure GBM histology and shorter survival (15.7 months versus 21.5 months). Nuclear expression of FABP7 was more specifically related to EGFR amplification and more invasive tumors. These data, although they need to be confirmed by further studies, support the relation between FABP7, astrocytic features, invasion and poor prognosis and suggests that EGFR amplification is associated with nuclear translocation of FABP7.

MGMT promoter methylation, which has been correlated with the response to alkylating agents, was investigated in a retrospective series of 219 glioblastomas (GBMs) treated with various modalities. MGMT methylation had no impact on survival for the whole group, but showed a significant advantage (17.1 months vs. 13.1) for patients treated with RT+ adjuvant chemotherapy (relative risk of death (RR) = 0.53; P = 0.041), particularly when patients received CT during the course of RT (MS = 19.9 months vs. 12.5 months; RR = 0.227, P = 0.001). This suggests that the prognostic impact of MGMT methylation is dependent on therapeutic modalities and schedules. MGMT methylation was not correlated with the main molecular alterations, such as 10q loss and p53 expression.

The methylation status of the O6-methylguanine-methyltransferase promoter (MGMTP) was evaluated in 68 low-grade gliomas treated by neoadjuvant temozolomide. Methylated MGMTP was detected in 63 of 68 (92.6 %) patients and was a favorable predictor of progression-free survival as compared with unmethylated MGMTP tumors (p < 0.0001). Assessment of MGMTP status could help identifying low-grade gliomas patients more likely to respond to chemotherapy or to benefit from MGMT depletion strategies.

Purpose of Review: This review focuses on recent advances in the molecular biology of the main primary brain tumors (gliomas, medulloblastomas, and ependymomas), with particular emphasis on prognostic markers and potential therapeutic targets., Recent Findings: Current biologic markers are useful for predicting prognosis (e.g. 1p/19q codeletion in grade 2 and 3 gliomas, nuclear beta-catenin expression in medulloblastoma) or response to the treatment (e.g. the methyl guanyl methyl transferase promoter methylation status). Recent gene profiling studies have identified specific molecular signatures that permit a molecular classification and that also provide new, potentially useful prognostic markers. The studies have also shown a striking parallel between central nervous system ontogenesis and the oncogenesis of brain tumors. By elucidating the underlying activated molecular pathways, these approaches provide the basis for a biologic therapy to target the critically activated pathways., Summary: Important advances have been made in the biologic understanding, molecular subclassification, and identification of prognostic markers in brain tumors, thereby improving the current classifications. Such data provide a rational basis for current and future targeted biologically based strategies.

Oligodendrogliomas have been the focus of considerable interest over the past decade, ever since they were recognized as chemosensitive tumors. They were once believed to represent less than 5% of gliomas, but by using expanded criteria, they may well represent up to one third. In fact, morphologic criteria are vague and highly subjective and the histologic diagnosis, therefore, remains highly controversial and unsatisfactory. New oligodendrocytic lineage markers, such as OLIG1/2 gene, will probably help to define the real spectrum of oligodendroglial tumors, which may include a wide variety of tumors with very different prognoses. Recently, genetic markers, and particularly loss of 1p and 19q chromosomes, have been shown to predict both prognosis and response to treatment. There is little doubt that these emerging techniques will be very helpful in clinical practice for refining both classification and therapeutic indications of oligodendroglial tumors.