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Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P < 0.0001) and overall survival (73.9 vs. 23.6 months; P < 0.0001). This effect was independent of grade, histologic subtype, and INA expression (P < 0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.

Ependymomas are glial neoplasms originating from the wall of the ventricles or from the spinal canal. The significance of histopathological features in accurately predicting biological behavior is still debated. Moreover, key molecular events in the pathogenesis of ependymoma are yet to be defined. The main objective of the present study was to identify specific patterns of chromosomal aberrations that correlate with tumor location, histological subtype and grade. Forty-five ependymoma samples were analyzed by 1-megabase resolution array comparative genomic hybridization (CGH). Association between clinical or histopathological parameters and the genomic alterations identified was evaluated. The most frequently detected chromosome (chr) abnormalities were gain of chr 7, 9, 12 and 15 and loss of chr 22. Co-occurrence of those five alterations characterized spinal ependymomas (P = 0.01). Myxopapillary ependymomas displayed a specific genomic profile defined by concurrent gain of chr 5, 7, 9, 16 and 18 (P = 0.0007). Overall, the number of chromosomal abnormalities detected was inversely correlated with the malignancy grade. Gain of chr 1q correlated with intracranial high-grade tumors (P = 0.002). Loss of chr 6q was mainly observed in infratentorial (P = 0.02) and World Health Organization (WHO) grade III (P = 0.04) lesions. Chr 10q loss was associated with high-grade ependymomas (P = 0.01). The +7/+9/+12/+15/-22 genomic profile is significantly associated with WHO grade II spinal ependymomas, whereas the +5/+7/+9/+16/+18 genomic pattern is specific of myxopapillary ependymomas. Identification of specific genomic imbalances at a given tumor location suggests that ependymomas from different central nervous system (CNS) regions represent genetically distinct diseases. Detecting genomic alterations associated with aggressive biological behavior may help stratify patients in high- and low-risk disease.

Using a one-megabase BAC-based array comparative genomic hybridization technique (aCGH), we have investigated a series of 16 low-grade gliomas (LGGs) and their subsequent progression to higher-grade malignancies. The most frequent chromosome imbalances in primary tumors were gains of chromosomes 7q, 8q, and 22q, and losses of chromosomes 1p, 13q, and 19q. In tumor progression, gains of chromosomes 11q, 7q, 20q, and 21q, and losses of chromosomes 9p, including CDKN2A locus, 19q, 14q, 1p, and 6q were the most frequent genomic disequilibria. Progressive tumors were more imbalanced than primary tumors in terms of altered chromosomal arms (3.8 vs. 6.6 in mean abnormal chromosomal arm) and altered BACs (17 vs. 21%). Interestingly, putative novel candidate genes associated with glioma progression were identified, in particular DOCK8, PTPRD, CER1, TPHO, DHFR, MSH3, ETS1, ACACA, and CSE1L.

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.

Loss of heterozygosity (LOH) of chromosome 22q has been investigated in 160 gliomas. LOH at one or more microsatellite increased with increasing grade of the tumor (P < 0.01). LOH22q was more frequent in astrocytic tumors (37%) compared to mixed or oligodendroglial tumors (21%) (P = 0.02). LOH22q was correlated to 10q loss but not to 1p or 9p loss. Taken together, these data suggest that LOH22q is an alteration associated with malignant progression of gliomas.

The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated. When evaluated in tumor samples, MRP1 expression was observed in all of them with more than 90% of stained tumor cells in 14/15 high-grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular endothelial cells in the same 14 tumor samples, suggesting that the permeability to anticancer drugs could be also limited across brain tumor vessels. At concentrations comprised between 5 and 50 microM, indomethacin significantly increased the cytotoxic effect of etoposide in both cell lines but it was more efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with 8MG cells. These results suggest that the association of indomethacin to VCR or etoposide could be of interest in the clinical management of gliomas.