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Research ArticleOriginal Article

Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma

Ruichao Chai, Guanzhang Li, Yuqing Liu, Kenan Zhang, Zheng Zhao, Fan Wu, Yuzhou Chang, Bo Pang, Jingjun Li, Yangfang Li, Tao Jiang and Yongzhi Wang
Cancer Biology & Medicine February 2021, 18 (1) 271-282; DOI: https://doi.org/10.20892/j.issn.2095-3941.2020.0179
Ruichao Chai
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Guanzhang Li
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Yuqing Liu
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Kenan Zhang
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Zheng Zhao
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Fan Wu
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Yuzhou Chang
2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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Bo Pang
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Jingjun Li
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Yangfang Li
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
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Tao Jiang
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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  • ORCID record for Tao Jiang
  • For correspondence: [email protected] [email protected]
Yongzhi Wang
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China
2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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  • For correspondence: [email protected] [email protected]
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    Figure 1

    The workflow and sample selection criteria of this study.

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    Figure 2

    The effect of IDH mutation on MGMT promoter methylation in GBM. (A) Heatmap showing the methylation levels of CpG sites 75–78 in the MGMT promoter in GBM samples with different IDH mutant status. For the MGMT promoter, the average methylation level of CpG sites 75–78 is denoted unmethy (unmethylated), <10%; weak methy (methylated), ≥10% and <30%; or methy, ≥30%. (B) The distribution of average methylation levels of CpG sites 75–78 was compared between IDH-wildtype and IDH-mutant GBM. ****P < 0.0001 calculated by the chi-square test. (C) The age of IDH-wildtype and IDH-mutant patients with GBM was compared. ****P < 0.0001 calculated by the nonparametric test. (D) The gender distribution was compared between IDH-wildtype and IDH-mutant patients with GBM.

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    Figure 3

    Survival analysis of IDH-mutant GBM with different MGMT promoter methylation levels. (A, B) Kaplan-Meier curves for PFS and OS of IDH-mutant patients with GBM in different methylation groups. (C, D) Kaplan-Meier curves for PFS and OS of IDH-mutant patients with GBM stratified by different cutoff values. (E, F) Kaplan-Meier curves for PFS and OS of IDH-wildtype patients with GBM in different methylation groups. (G, H) Kaplan-Meier curves for PFS and OS of IDH-wildtype patients with GBM stratified by different cutoff values. P-value calculated by the log-rank test. MGMT promoter methylation levels were calculated on the basis of the average methylation levels of CpG sites 75–78.

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    Figure 4

    Validation of the predictive value of MGMT promoter methylation in another cohort of TMZ treated IDH-mutant GBM. (A) Kaplan-Meier curves for PFS of IDH-mutant patients with GBM in different methylation groups. (B) Kaplan-Meier curves for PFS of IDH-mutant patients with GBM, stratified by different cutoff values. (C) Kaplan-Meier curves for OS of IDH-mutant patients with GBM in different methylation groups. (D) Kaplan-Meier curves for OS of IDH-mutant patients with GBM, stratified by different cutoff values. P-value calculated by the log-rank test. MGMT promoter methylation levels were calculated on the basis of the average methylation levels of CpG sites 76–79.

Tables

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    Table 1

    Characteristics of IDH-mutant patients with GBM used in survival analysis

    Cohort A (CpGs 75–78, n = 50)Cohort B (CpGs 76–79, n = 25)P
    Median age (range)41 (26–63)43 (29–66)0.3887a
    Gender1.0000b
     Male3060.0%1560.0%
     Female2040.0%1040.0%
    Type0.4091b
     Primary2346.0%936.0%
     Recurrent/secondary2754.0%1664.0%
    Resection0.0228b
     Gross total3366.0%832.0%
     Subtotal1632.0%1352.0%
     Unknown12.0%416.0%
    Median KPS (range)70 (50–90)70 (50–90)0.5464b
     <701734.0%936.0%
     ≥702244.0%1664.0%
     Unknown1122.0%00.0%
    TMZ cycles0.8511b
     ≥3 and <61326.0%624.0%
     ≥63774.0%1976.0%
    MGMT promoter methylation0.5431b
     ≥30%1428.0%1144.0%
     ≥20%, <30%816.0%416.0%
     ≥10%, <20%1632.0%624.0%
     <10%1224.0%416.0%
    Median PFS (months)10.578.320.5711c
    Median OS16.1313.20.3240c

    aCalculated by the nonparametric test; bCalculated by the chi-square test; cCalculated by the log-rank test in Kaplan-Meier curves.

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      Table 2

      Comparison of characteristics of IDH-mutant GBM samples with or without MGMT methylation (cutoff ≥30%) in cohort A

      Unmethylated (n = 35)Methylated (n = 15)P
      Median age (range)41 (26–63)39 (33–62)0.4529a
      Gender0.2077b
       Male2365.7%746.7%
       Female1234.3%853.3%
      Type0.1935b
       Primary1440.0%960.0%
       Recurrent2160.0%640.0%
      Resection0.1053b
       Gross total2674.3%853.3%
       Subtotal822.9%746.7%
       Unknown12.9%00.0%
      TMZ cycles0.9706b
       ≥3 and <6925.7%426.7%
       ≥63085.7%1386.7%
      KPS0.6479b
       <701234.3%533.3%
       ≥701440.0%853.3%
       Unknown925.7%213.3%
      Median PFS (months)9.3326.040.0012c
      Median OS (months)13.135.80.0004c

      aCalculated by the nonparametric test; bCalculated by the chi-square test; cCalculated by the log-rank test in Kaplan-Meier curves.

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        Table 3

        Univariate and multivariate Cox regression analysis in cohort A

        Univariate Cox analysisMultivariate Cox analysis
        PHR95% CI for HRPHR95% CI for HR
        LowerHigherLowerHigher
        Age0.7610.9950.9631.028––––
        Gender (female vs. male)0.2230.6630.3431.283––––
        MGMT (unmethy vs. methy)0.0013.6911.6898.0630.0023.5601.6007.920
        Extent of resection (total vs. subtotal)0.4701.2870.6492.549––––
        Type (primary vs. recurrent/secondary)0.0050.3660.1820.7330.0100.3840.1860.794

        HR, hazard ratio; CI, confidence interval; methy, methylated; unmethy, unmethylated.

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        Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma
        Ruichao Chai, Guanzhang Li, Yuqing Liu, Kenan Zhang, Zheng Zhao, Fan Wu, Yuzhou Chang, Bo Pang, Jingjun Li, Yangfang Li, Tao Jiang, Yongzhi Wang
        Cancer Biology & Medicine Feb 2021, 18 (1) 271-282; DOI: 10.20892/j.issn.2095-3941.2020.0179

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        Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma
        Ruichao Chai, Guanzhang Li, Yuqing Liu, Kenan Zhang, Zheng Zhao, Fan Wu, Yuzhou Chang, Bo Pang, Jingjun Li, Yangfang Li, Tao Jiang, Yongzhi Wang
        Cancer Biology & Medicine Feb 2021, 18 (1) 271-282; DOI: 10.20892/j.issn.2095-3941.2020.0179
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        • Brain Tumor

        Keywords

        • Glioblastoma
        • O6methylguanine-DNA methyltransferase
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        • temozolomide
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