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Defining optimal cutoff value of MGMT promoter methylation by ROC analysis for clinical setting in glioblastoma patients.

Al's Comment:

Until recently, this did not matter much, but as we get closer to treatments that can work on patients with unmethylated MGMT, this becomes of utmost importance.    To recap:  MGMT is a repair enzyme that can fix the damage caused by Temozolomide, making the cells resistant to Temozolomide. "Methylation of MGMT" means that the gene that codes for the MGMT repair enzyme is blocked so it cannot make the MGMT enzyme - which gives a better result for Temozolomide.   "Unmethylated MGMT" thus means that the gene is not blocked, and it makes the repair enzyme, so Temozolomide has much less chance of helping.  The controversy is that most tests do not say you are 100% methylated or unmethylated.  It is open to interpretation of where the cutoff between methylated and unmethylated lies.  Pathology labs should show the % of methylated cells in addition to the label of unmethylated or methylated, as this cutoff value can change.


Posted on: 05/20/2017

  J Neurooncol. 2017 May 17. doi: 10.1007/s11060-017-2433-9. [Epub ahead of print]

Defining optimal cutoff value of MGMT promoter methylation by ROC analysis for clinical setting in glioblastoma patients.

Yuan G1, Niu L2, Zhang Y2, Wang X1, Ma K3, Yin H2, Dai J2, Zhou W4, Pan Y5,6.
 
Author information:
1
    Neurology Institute, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China.
2
    Department of Neurosurgery, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China.
3
    Center Laboratory, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China.
4
    Department of Neurosurgery, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China. zhouwangningldey@sina.cn.
5
    Neurology Institute, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China. panyawen666@sohu.com.
6
    Department of Neurosurgery, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China. panyawen666@sohu.com.
 
Abstract
 
Resistance to temozolomide (TMZ) chemotherapy poses a significant challenge in the treatment of glioblastoma (GBM). Hypermethylation in O6-methylguanine-DNA methyltransferase (MGMT) promoter is thought to play a critical role in this resistance. Pyrosequencing (PSQ) has been shown to be accurate and robust for MGMT promoter methylation testing. The unresolved issue is the determination of a cut-off value for dichotomization of quantitative MGMT PSQ results into "MGMT methylated" and "MGMT unmethylated" patient subgroups as a basis for further treatment decisions. In this study, receiver operating characteristic (ROC) curve analysis was used to identify an optimal cutoff of MGMT promoter methylation by testing mean percentage of methylation of 4 CpG islands (76-79) within MGMT exon 1. The area under the ROC (AUC) as well as the best cutoff to classify the methylation were calculated. Positive likelihood ratio (LR+) was chosen as a diagnostic parameter for defining an optimal cut-off. Meanwhile, we also analyzed whether mean percentage of methylation at the investigated CpG islands could be regarded as a marker for evaluating prognostication. ROC analysis showed that the optimal threshold was 12.5% (sensitivity: 60.87%; specificity: 76%) in response to the largest LR+ 2.54. 12.5% was established to distinguish MGMT promoter methylation, which was confirmed using validation set. According to the cutoff value, the MGMT promoter methylation was found in 58.3% of GBM. Mean methylation level of the investigated CpG sites strong correlated with overall survival (OS), which means GBM patients with a high level of methylation survived longer than those with low level of methylation(log-rank test, P = 0.017). In conclusion, ROC curve analysis enables the best cutoff for discriminating MGMT promoter methylation status. LR+ can be used as a key factor that evaluates cutoff. The promoter methylation level of MGMT by PSQ in GBM patients had prognostic value.
PMID: 28516344
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