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Pasini A.,University of Bologna | Iorio P.,Gruppo Neuroncologico Romagnolo GNR | Iorio P.,M Bufalini Hospital | Bianchi E.,Gruppo Neuroncologico Romagnolo GNR | And 16 more authors.
Oncology Reports | Year: 2012

We previously described a cohort of grade II oligodendroglioma (OII) patients, in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at a higher risk of relapse. In this study, we evaluated the CpG methylation of the putative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoter in the same OII cohort, to investigate whether a correlation could be found between EMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-three tumor samples from OII patients were collected over a period of 10 years. Seventeen glioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients. The EMP3, O 6-methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2) promoter methylation, evaluated by methylation-specific PCR, and the isocitrate dehydrogenase 1 (I DH1) mutation, identified by sequencing, were compared between the OII and GBM histotypes. The EMP3 promoter methylation was correlated with the analysis of LOH 19q, performed by microsatellite amplification, in OII patients. Disease progression-free interval was evaluated in the OII patients with the EMP3 methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 and MGMT promoter methylation was more frequent in OII than in GBM patients, and the IDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes. Both LOH+/-19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19q and EMP3 gene promoter methylation was observed in the OII patients at a higher risk of relapse. Our results suggest that a total (cytogenetic and epigenetic) functional loss of both EMP3 alleles accounts for the reduced disease progression-free interval in OII patients. Although the small sample size limits the strength of this study, our results support testing this hypothesis in larger cohorts of patients, considering the methylation of the EMP3 gene promoter together with LOH 19q as an indication for treatment with adjuvant therapy ab initio in order to improve the overall survival of OII patients.

Molinari C.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Iorio P.,Gruppo Neuroncologico Romagnolo GNR | Iorio P.,Bufalini Hospital | Medri L.,Morgagni Pierantoni Hospital | And 15 more authors.
International Journal of Molecular Medicine | Year: 2010

Oligodendrogliomas are rare primary brain tumors with variable patient outcomes which are not always adequately accounted for by clinical or pathological variables. The present study evaluated the prognostic implications of chromosome 1p and 19q status in a set of 23 low grade oligodendrogliomas (OGD II), and correlated the results with patient outcome. Loss of heterozygosity (LOH) and fluorescent in situ hybridization (FISH) analyses, the most widely used standard procedures, were used. 1p and 19q deletions were found in 65 and 61% of cases, respectively, using FISH and in 78 and 72% of cases using LOH. Both deletions were found in 56 and 64% of patients using FISH and LOH, respectively. Concordance between the results from the two techniques, determined by the Kappa statistics, ranged from fair to substantial depending on whether single or combined deletions were considered. Our results showed that the molecular alterations are associated with age and tumor localization. With regard to the impact of chromosomal alterations on clinical outcome, chromosome 19q deletions detected by LOH would seem to indicate a subgroup of patients at a higher risk of relapse, although the small number of patients recruited does not permit any definitive conclusions to be drawn. Further studies are now ongoing to determine whether this methodological approach could be potentially useful in low grade oligodendrogliomas to better characterize chromosomal alterations of 1p/19q and identify subgroups of patients with a higher risk of disease recurrence.

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