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

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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.

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Abbreviations

GBM:

Glioblastoma

PSQ:

Pyrosequencing

ROC:

Receiver operating characteristic

AUC:

Area under the ROC

LR+:

Positive likelihood ratio

OS:

Overall survival

TMZ:

Temozolomide

MGMT:

O6-methylguanine-DNA methyltransferase

GTR:

Gross total resection

PR:

Partial resection

KPS:

Karnofsky Performance Scale

HR:

Hazard ratio

CI:

Confidence interval

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Acknowledgements

Funding was provided by Research Project of Chinese Society of Neuro-oncology (Grant No. CSNO-2013-MS008). The Project of Healty and Famliy Planing Commission of Gansu (Grant No. GSWSKY-2015-58/-2014-31), the Lanzhou Science and Technology Bureau Project (Grant No. 2013-3-27/2015-3-86), and the doctoral research fund of Lanzhou University Second Hospital (Grant No. ynbskyjj 2015-1-02/2015-2-11/2015-2-5)

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Authors and Affiliations

  1. Neurology Institute, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China

    Guoqiang Yuan, **aoqing Wang & Yawen Pan

  2. Department of Neurosurgery, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China

    Liang Niu, Yinian Zhang, Hang Yin, Junqiang Dai, Wangning Zhou & Yawen Pan

  3. Center Laboratory, The Second Hospital, Lanzhou University, Lanzhou, 730030, Gansu, China

    Kejun Ma

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  1. Guoqiang Yuan
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Correspondence to Wangning Zhou or Yawen Pan.

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Yuan, G., Niu, L., Zhang, Y. et al. Defining optimal cutoff value of MGMT promoter methylation by ROC analysis for clinical setting in glioblastoma patients. J Neurooncol 133, 193–201 (2017). https://doi.org/10.1007/s11060-017-2433-9

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