Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts

Abstract

Introduction: Recent studies suggest an overrepresentation of MGMT promoter methylated tumors in females with IDHwt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment. Methods: To reveal sex-bound associations that may have gone unnoticed in the original analysis, we re-analyzed two previously published clinical cohorts. One was the multicenter Nordic trial of elderly patients with GBM, randomizing patients into three different treatment arms, including 203 cases with known MGMT promoter methylation status. The other was a population-based study of 179 patients with IDHwt GBM, receiving concomittant radiotherapy and chemotherapy with temozolomide. Cohorts were stratified by sex to test the hypothesis that female sex in combination with MGMT promoter methylation constitutes a subgroup with more favorable outcome. Results: There was a significantly larger proportion of MGMT promoter methylation and better outcome for female patients with MGMT promoter methylated tumors. Results were confirmed in 257 TCGA-derived IDHwt GBM with known sex and MGMT status. Conclusions: These results confirm that patient sex in combination with MGMT promoter methylation is a key determinant in GBM to be considered prior to treatment decisions. Our study also illustrates the need for stratification to identify such sex-bound associations.

Sex Differences in Glioblastoma—Findings from the Swedish National Quality Registry for Primary Brain Tumors between 1999–2018

“…In the same study, surprisingly, the methylated MGMT promoter was not a significant factor for survival for male patients treated with alkylating agents. We, together with others, have reported that a larger proportion of women with GBM have MGMT promoter methylated tumors, approximately 50%, in comparison to only around one third in men [10][11][12]19]. Apart from this, our data seem to support women having a better response to alkylating agent treatment when the MGMT promoter is methylated.…”

“…As a consequence, this has led to an increased understanding of the basic sex differences, identified for mutations [6] and methylation profiles [7], followed by transcriptomes [8] and tumor metabolism [9]. In addition, an influence in the proportion of patients being MGMT promoter methylated and response to alkylating agent treatment in a sex specific manner have been identified [10]. Whether survival is affected by these disparities is debated [8,[11][12][13].…”

Serum microRNA-4297 is a sex-specific predictive biomarker of glioma grade and prognosis

“…Although the underlying sex-bound association remained elusive, growing research has focused on that sex plays a vital role in glioma initiation and progression. The significantly larger proportion of MGMT promoter methylation and better outcomes for female patients has gained the attention of researchers ( 37 ). As compared to males, our present study presented the prominent increase of serum miR-4297 in parallel with MGMT protein on tumor tissues in females, which is probably attributed to sex disparities in MGMT expression in glioma.…”

Radiomics-based neural network predicts recurrence patterns in glioblastoma using dynamic susceptibility contrast-enhanced MRI

“…Recently, sex difference has been revealed to be existent in treatment response of glioblastoma 39 . Smits et al reported that female sex in combined with MGMT methylation—epigenetic silencing for DNA repair of tumor after temozolomide treatment, which has been shown to be more sensitive to chemotherapy 40 , 41 —showed more favorable outcome to standard therapy 39 , 42 . However, in our result, sex was not significant prognostic factor when removing MGMT status from the Cox model or not.…”