© 2004 by Society
© 2004 by the Society forNeuro-Oncology
Intercellular heterogeneity of expression of the MGMT DNA repairgene in pediatric medulloblastoma
Children's Research Institute, Children's NationalMedical Center, Washington, DC 20010 (B.R.R., H.Z.); Department of Pediatrics, Institute for BiomedicalSciences, The George Washington University Medical Center, Washington, DC20037 (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, DC20010, USA(Brood{at}CNMC.org).
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Abstract |
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DNA methylation and epigenetic inactivation of theO6-methylguanine methyltransferase (MGMT) geneinduces MGMT deficiency, reducing the tumor cell's DNA repair capacity andincreasing its susceptibility to alkylating chemotherapeutic agents.Consequently, adult patients whose tumors are deficient in MGMT have betteroutcomes with alkylator chemotherapy, and MGMT methylation has beenproposed as a screening marker of deficient tumors. In order to test thefeasibility of this approach for medulloblastoma, a common brain tumor inchildren, we determined the methylation status, mRNA expression pattern, andprotein expression of MGMT in a panel of clinical specimens.Methylation-specific polymerase chain reaction analysis revealed methylationof MGMT in 28 of 37 tumor samples. Quantitative real-time reversetranscriptase-polymerase chain reaction showed a range of expression ofMGMT mRNA varying more than 20-fold. However, there was nocorrelation found between MGMT methylation and mRNA expression.Immunohistochemistry demonstrated that all tumors were immunoreactive for MGMTin the nucleus of the medulloblastoma cells in a heterogeneous pattern. Theintercell variability of MGMT complement explained the discordance betweenmethylation and expression. Therefore, MGMT methylation as determinedby methylation-specific polymerase chain reaction cannot be used as a markerfor MGMT deficiency in medulloblastoma. Further, these findings support theuse of pharmacological MGMT depletion as a rational approach forintensification of alkylator chemotherapy in the treatment ofmedulloblastoma.
Received October 14, 2004; Accepted March 3, 2004
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