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

Abstract

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 (06-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 sub-populations 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.

Changes of O6-Methylguanine DNA Methyltransferase (MGMT) Promoter Methylation in Glioblastoma Relapse—A Meta-Analysis Type Literature Review

“…The observed changes were almost equally distributed to losses (n = 16) and gains (n = 11) of MGMT promoter methylation, suggesting TMZ to possibly not be causing a significant selection pressure. This view is shared by Storey et al, who recently proposed a mathematical model to predict GBM response to TMZ treatment [64]. They conclude that the changes in methylation cannot be explained by evolutionary selection alone, but might indeed occur due to TMZ altering the cells' general methylation profile.…”

“…Again, the results of the different studies are contradictory. While some did not see a correlation between TMZ treatment and a change of MGMT promoter methylation [47,49], others drew a different conclusion [48,64]. The subgroup of patients with methylated MGMT promoter in the primary tumor displayed a significant loss of methylation if treated with concurrent RT/TMZ (7 of 8) compared to patients treated with RT followed by sequential TMZ (1 of 5, p = 0.03).…”

FoxD2-AS1is a prognostic factor in glioma and promotes temozolomide resistance in a O6-methylguanine-DNA methyltransferase-dependent manner

“…However, a majority of patients with glioma gradually develop resistance to TMZ during treatment. The most popular mechanism of TMZ resistance is the expression of O 6 -methylguanine-DNA methyltransferase (MGMT) which removes the cytotoxic O 6 -methylguanine-DNA adducts [56]. The expression of MGMT is regulated by MGMT promoter methylation.…”

Introduction to Mathematical Oncology

“…Continuing the theme of studying intratumoral cell population dynamics and treatment, Storey et al 23 present a multitype, continuous-time, birth–death, process-based model to study the dynamics of genome methylation in glioblastoma recurrence. The authors focused on the methylation of the promoter region of the DNA repair gene methylguanine methyltransferase ( MGMT ), which has been associated with sensitivity to the standard-of-care chemotherapy temozolomide (TMZ).…”