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Intercellular heterogeneity of expression of the MGMT DNA repair gene in pediatric medulloblastoma

Children's Research Institute, Children's National Medical Center, Washington, DC 20010 (B.R.R., H.Z.); Department of Pediatrics, Institute for Biomedical Sciences, The George Washington University Medical Center, Washington, DC 20037 (P.H.C.); USA

² Address correspondence to Brian R. Rood, Division of Hematology/Oncology, Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010, USA (Brood{at}CNMC.org).

Abstract

DNA methylation and epigenetic inactivation of the O⁶-methylguanine methyltransferase (MGMT) gene induces MGMT deficiency, reducing the tumor cell's DNA repair capacity and increasing its susceptibility to alkylating chemotherapeutic agents. Consequently, adult patients whose tumors are deficient in MGMT have better outcomes with alkylator chemotherapy, and MGMT methylation has been proposed as a screening marker of deficient tumors. In order to test the feasibility of this approach for medulloblastoma, a common brain tumor in children, we determined the methylation status, mRNA expression pattern, and protein expression of MGMT in a panel of clinical specimens. Methylation-specific polymerase chain reaction analysis revealed methylation of MGMT in 28 of 37 tumor samples. Quantitative real-time reverse transcriptase-polymerase chain reaction showed a range of expression of MGMT mRNA varying more than 20-fold. However, there was no correlation found between MGMT methylation and mRNA expression. Immunohistochemistry demonstrated that all tumors were immunoreactive for MGMT in the nucleus of the medulloblastoma cells in a heterogeneous pattern. The intercell variability of MGMT complement explained the discordance between methylation and expression. Therefore, MGMT methylation as determined by methylation-specific polymerase chain reaction cannot be used as a marker for MGMT deficiency in medulloblastoma. Further, these findings support the use of pharmacological MGMT depletion as a rational approach for intensification of alkylator chemotherapy in the treatment of medulloblastoma.

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