Glioblastoma Recurrence and the Role of O⁶-Methylguanine–DNA Methyltransferase Promoter Methylation

Feb 14, 2019JCO clinical cancer informatics

Glioblastoma Return Linked to Changes in DNA Repair Gene Control

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Abstract

A mathematical model indicates that the downward shift in MGMT promoter methylation from primary to recurrent glioblastoma tumors cannot be solely explained by evolutionary selection.

MGMT methylation is linked to sensitivity to temozolomide (TMZ), while increased MGMT expression is associated with resistance.
Clinical observations show a decrease in MGMT methylation percentage from primary to recurrent tumors.
The model suggests that TMZ inhibits the maintenance of MGMT methylation after cell division.
Optimal dosing strategies for TMZ may vary based on initial MGMT methylation levels in patients.

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Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O-methylguanine-DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM-surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis. 6

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Glioblastoma Recurrence and the Role of O⁶-Methylguanine–DNA Methyltransferase Promoter Methylation

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