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The Clinical Implications of Inconsistently Methylated Results from Glioblastoma MGMT Testing by Replicate Methylation-Specific PCR.

Al's Comment:

 Excellent article. Apparently, when the MGMT methylation status test results show inconsistent methylation, it really should be thought of as being unmethylated.  For background:  MGMT is a gene that codes for an enzyme that repairs damage to the DNA caused by Temodar.  If your MGMT genes are methylated, that means they are inactive and can not produce the repair enzyme.  This makes Temodar work much better.  However, if your MGMT is unmethylated  (or apparently now - even inconclusive), the repair enzyme is produced which reverses the damage caused by Temodar, making it not really work.

This really didn't matter much until recently when a new drug, Val-083, was created which works similar to Temodar but on a different part of the DNA so that this repair enzyme can not reverse the damage. This drug is about to start phase 3 clinical trials. Worth considering for those whose test show unmethylated MGMT. 

Posted on: 09/21/2016

J Mol Diagn. 2016 Sep 14. pii: S1525-1578(16)30139-8. doi: 10.1016/j.jmoldx.2016.06.009. [Epub ahead of print]
The Clinical Implications of Inconsistently Methylated Results from Glioblastoma MGMT Testing by Replicate Methylation-Specific PCR.
Xia D1, Reardon DA2, Bruce JL3, Lindeman NI3.
Author information:
1Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:
2Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
The methylation status of the promoter of the O6-methylguanine DNA methyltransferase gene (MGMT) is an established prognostic and predictive biomarker of glioblastoma (GBM). At the Center for Advanced Molecular Diagnostics, MGMT testing is performed by methylation-specific PCR with multiple replicates, leading to three types of reportable results: methylated, unmethylated, and inconsistently methylated. An inconsistently methylated result is reported when a methylated peak is seen in some but not all of the PCR replicates from a single DNA sample. To better understand the clinical implications of these results, we performed a retrospective review of all MGMT testing at our laboratory over a 5-year period, and correlated test results with outcome and specimen-quality data. This review yielded several novel findings. First, inconsistent MGMT methylation on replicate methylation-specific PCR is not uncommon, composes 12% (58/465) of our GBM results. Second, inconsistently methylated GBM cases are associated with relatively poor overall survival (more similar to unmethylated than to methylated cases). Third and interestingly, there appears to be a dose-response relationship between patient survival and the extent of methylation in inconsistently methylated GBMs. Finally, our analyses of specimen-quality data suggest that a combination of technical factors (eg, small samples) and tumor biology may explain inconsistent MGMT results on replicate methylation-specific PCR testing.
Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
PMID: 27639200 [PubMed - as supplied by publisher]
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