PURPOSE: O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined. METHODS: We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens. RESULTS: Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location. CONCLUSION: Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.
PURPOSE:O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined. METHODS: We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens. RESULTS: Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location. CONCLUSION: Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.
Authors: A K Annamalai; A F Dean; N Kandasamy; K Kovacs; H Burton; D J Halsall; A S Shaw; N M Antoun; H K Cheow; R W Kirollos; J D Pickard; H L Simpson; S J Jefferies; N G Burnet; M Gurnell Journal: Pituitary Date: 2012-09 Impact factor: 4.107
Authors: Ian F Pollack; Ronald L Hamilton; Robert W Sobol; Marina N Nikiforova; Yuri E Nikiforov; Maureen A Lyons-Weiler; William A LaFramboise; Peter C Burger; Daniel J Brat; Marc K Rosenblum; Floyd H Gilles; Allan J Yates; Tianni Zhou; Kenneth J Cohen; Jonathan L Finlay; Regina I Jakacki Journal: Pediatr Blood Cancer Date: 2010-12-01 Impact factor: 3.167
Authors: Rahul D Tendulkar; Atmaram S Pai Panandiker; Shengjie Wu; Larry E Kun; Alberto Broniscer; Robert A Sanford; Thomas E Merchant Journal: Int J Radiat Oncol Biol Phys Date: 2010-03-24 Impact factor: 7.038