O6- Methylguanine-DNA-Methyltransferase in Recurring Anaplastic Ependymomas: PCR and Immunohistochemistry

Abstract

Ependymomas are the third most common brain tumor in children. The post surgical management is controversial. There are no convincing data on an effective role for chemotherapy. O(6)-Methylguanine-DNA-Methyltransferase (MGMT) is a DNA repair protein considered to be a chemosensitivity predictor. Hypermethylation of the MGMT gene promoter is an important cause of MGMT inactivation. We evaluated the MGMT gene promoter methylation and the immunohistochemical MGMT protein expression in 12 recurrent anaplastic ependymomas affecting children. Our purpose was to investigate the molecular rationale of the administration of alkylating agents to children affected by recurrent anaplastic ependymomas. All ependymomas lacked MGMT promoter hypermethylation and 9 (75%) showed high MGMT protein expression (>50% tumoral cells). Differences between different recurrences in the same patient were not observed. These results may indicate MGMT as a factor of chemoresistance to alkylating drugs in anaplastic ependymomas and support the uncertainties regarding the actual benefit of chemotherapy for patients with anaplastic ependymomas.

Ependymomas in Adults

“…The report by Chamberlain and Johnston [48] showed minimal activity, whereas the ongoing study at the University of Torino has shown promising early results [50]. However, recent reports suggest that a large percentage of ependymomas express high levels of MGMT, an enzyme that confers resistance to alkylating agents such as temozolomide [32]. This suggests that alternative schedules, such as more prolonged, dosedense schedules, may have improved efficacy because these have been shown to deplete MGMT in peripheral blood lymphocytes.…”

“…Similarly, overexpression of the α v β 3 integrin was found in a high percentage of ependymomas, and there now are specific agents targeting this integrin [21]. The finding that most ependymomas overexpress MGMT may provide insight into the overall poor response of ependymoma to conventional cytotoxic chemotherapy, as this enzyme is a major mechanism of resistance to alkylating agents [32]. Therefore, strategies to modulate MGMT activity may have benefit in ependymomas.…”

Pediatric Ependymoma: Biological Perspectives

“…Pediatric glioblastoma stem cells display resistance to radiation because of preferential activation of the DNA damage checkpoint (163,164), whereas xenograft models have attributed varying radiation resistance between ependymomas to possible inherent differences in p53 mediated growth arrest (160). Overexpression of the DNA repair protein and chemosensitivity marker MGMT in a small series of recurrent pediatric ependymomas suggests a possible implication in anaplastic ependymoma chemoresistance (165). Additionally, distinct populations of forebrain neural stem and progenitor cells can be isolated on the basis of their ability to efflux the fluorescent dye Hoechst 33342, indicative of high expression of ATP-binding cassette (ABC) drug transporters (166,167).…”

Merlin Expression in Pediatric Anaplastic Ependymomas Real Time PCR Study

“…Nevertheless, it has been demonstrated that the histological tumor grade is also a predictor of the clinical behavior. Actually, WHO III anaplastic ependymomas show an unfavorable outcome [3].…”

“…Eight (50%) were from men and 8 (50%) were from women. The average age at the time of the first surgery at our institution was 7 years (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] …”