Association of MGMT Promoter and Enhancer Methylation with Genetic Variants, Clinical Parameters, and Demographic Characteristics in Glioblastoma

Katja Zappe, Katharina Pühringer, Simon Pflug, Daniel Berger, Serge Weis, Sabine Spiegl-Kreinecker, Margit Cichna-Markl (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

The response of glioblastoma (GBM) patients to the alkylating agent temozolomide (TMZ) vitally depends on the expression level of the repair protein O6-methylguanine-DNA methyltransferase (MGMT). Since MGMT is strongly regulated by promoter methylation, the methylation status of the MGMT promoter has emerged as a prognostic and predictive biomarker for GBM patients. By determining the methylation levels of the four enhancers located within or close to the MGMT gene, we recently found that enhancer methylation contributes to MGMT regulation. In this study, we investigated if methylation of the four enhancers is associated with SNP rs16906252, TERT promoter mutations C228T and C250T, TERT SNP rs2853669, proliferation index Ki-67, overall survival (OS), age, and sex of the patients. In general, associations with genetic variants, clinical parameters, and demographic characteristics were caused by a complex interplay of multiple CpGs in the MGMT promoter and of multiple CpGs in enhancer regions. The observed associations for intragenic enhancer 4, located in intron 2 of MGMT, differed from associations observed for the three intergenic enhancers. Some findings were restricted to subgroups of samples with either methylated or unmethylated MGMT promoters, underpinning the relevance of the MGMT promoter status in GBMs.

Original languageEnglish
Article number5777
JournalCancers
Volume15
Issue number24
DOIs
Publication statusPublished - Dec 2023

Austrian Fields of Science 2012

  • 302055 Oncology
  • 301904 Cancer research

Keywords

  • age
  • biomarker
  • DNA methylation
  • enhancer methylation
  • glioblastoma
  • Ki-67
  • MGMT
  • overall survival
  • promoter methylation

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