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Research Article

Potent predictive CpG signature for temozolomide response in non-glioma-CpG island methylator phenotype glioblastomas with methylated MGMT promoter

    Jiu Wang‡

    Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    ‡Authors contributed equally

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    ,
    Meng Zhang‡

    Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, 710032, Shaanxi

    ‡Authors contributed equally

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    ,
    Yi-feng Liu‡

    Department of Biochemistry & Molecular Biology, Fourth Military Medical University, Xi’an, 710032, China

    ‡Authors contributed equally

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    ,
    Yan Yao‡

    Department of Biochemistry & Molecular Biology, Fourth Military Medical University, Xi’an, 710032, China

    ‡Authors contributed equally

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    ,
    Yu-sha Ji

    Department of Biochemistry & Molecular Biology, Fourth Military Medical University, Xi’an, 710032, China

    ,
    Amandine Etcheverry

    CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR), Rennes F-35043, France

    ,
    Kun Chen

    Department of Anatomy, Histology & Embryology & K.K. Leung, Brain Research Centre, School of Basic Medicine, Fourth Military Medical University, Xi’an, 710032, China

    ,
    Bao-qiang Song

    Department of Plastic & Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    ,
    Wei Lin

    Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    ,
    Anan Yin

    *Author for correspondence:

    E-mail Address: yinanan@aliyun.com

    Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Department of Biochemistry & Molecular Biology, Fourth Military Medical University, Xi’an, 710032, China

    Department of Plastic & Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    &
    Ya-long He

    **Author for correspondence:

    E-mail Address: heyl.fmmu@hotmail.com

    Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Published Online:https://doi.org/10.2217/epi-2022-0344

    Aim: We aimed to identify potent CpG signatures predicting temozolomide (TMZ) response in glioblastomas (GBMs) that do not have the glioma-CpG island methylator phenotype (G-CIMP) but have a methylated promoter of MGMT (meMGMT). Materials & methods: Different datasets of non-G-CIMP meMGMT GBMs with molecular and clinical data were analyzed. Results: A panel of 77 TMZ efficacy-related CpGs and a seven-CpG risk signature were identified and validated for distinguishing differential outcomes to radiotherapy plus TMZ versus radiotherapy alone in non-G-CIMP meMGMT GBMs. An integrated classification scheme was also proposed for refining a MGMT-based TMZ-guiding approach in all G-CIMP-GBMs. Conclusion: The CpG signatures may serve as promising predictive biomarker candidates for guiding optimal TMZ usage in non-G-CIMP meMGMT GBMs.

    Plain language summary

    Glioblastomas that do not have the glioma-CpG island methylator phenotype (G-CIMP) but have a methylated promoter of the MGMT gene (meMGMT) show considerable variability in their response to temozolomide (TMZ). Powerful biomarkers that provide predictive information on optimal TMZ decision-making can be clinically useful. This study has identified and validated a panel of 77 TMZ efficacy-related CpGs and a seven-CpG risk signature for predicting TMZ usage in non-G-CIMP meMGMT glioblastomas. An integrated classification scheme is proposed for refining a MGMT-based TMZ-guiding approach in non-G-CIMP glioblastomas.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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