TITLE

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

AUTHOR(S)
Rood, Brian R.; Huizhen Zhang; Cogen, Philip H.
PUB. DATE
July 2004
SOURCE
Neuro-Oncology;Jul2004, Vol. 6 Issue 3, p200
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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 bet-ter outcomes with alkylator chemotherapy, and MGMT methylation has been propo-sed 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 demon-strated that all tumors were immunoreactive for MGMT in the nucleus of the medu-lloblastoma cells in a heterogeneous pattern. The intercell variability of MGMT comp-lement explained the discordance between methylation and expression. Therefore, MGMT methylation as determined by methylationspecific 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.
ACCESSION #
16912260

 

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