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Intercellular heterogeneity of expression of
the MGMT DNA repair gene in pediatric medulloblastoma
Brian R. Rood, Huizhen Zhang, Philip H. Cogen
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
DNA methylation and epigenetic inactivation of the O 6-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 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.
© 2004 Duke University Press
Source: http://fiordiliji.ingentaselect.com/vl=2561976/cl=15/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n3/s3/p200
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