Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

Abstract

Asian Pac J Cancer Prev, 15 (24), 10893-10898 IntroductionGlioblastoma multiform (GBM), classified as World Health Organization (WHO) grade IV, is the most common malignant brain tumors in adults with an incidence rate of 23 per 100,000 persons (Stancheva et al., 2014). Their clinical course varies substantially, such that some patients succumb to progressive disease within weeks while others survive for a decade or more. Current treatments include surgery, radiation therapy and chemotherapy (Sathornsumetee et al., 2007;Koca et al., 2014;Pashaki et al., 2014). However, the median survival is still not optimistic. In spite of the existing classification, GBM subgroups are not homogeneous in terms of survival (Molenaar et al., 2014). Several prognostic factors have been established, including age, preoperative Karnofsky Performance Status (KPS), extent of resection, and also some molecular markers.Recently, molecular markers were shown to be helpful in predicting prognosis and treatment response. Three gene markers that have attracted most interest in this respect are mutations in the isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) gene (Stancheva et al., 2014), hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter, and complete deletion of both 1p and 19q. Abstract Several molecular markers have been proposed as predictors of outcome in patients with glioblastomas.We investigated the prognostic significance of O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation and TP53 mutation status dependent on isocitrate dehydrogenase 1 (IDH1) mutation in glioblastoma patients. A cohort of 78 patients with histologically confirmed glioblastomas treated with radiation therapy and chemotherapy were reviewed retrospectively. We evaluated the prognostic value of MGMT promoter methylation and TP53 mutation status with regard to progression-free survival (PFS) and overall survival (OS). It was revealed that mutations in IDH1, promoter methylation of MGMT, TP53 mutation, age, Karnofsky performance status (KFS), and extension of resection were independent prognostic factors. In patients with an IDH1 mutation, those with an MGMT methylation were associated with longer PFS (p=0.016) and OS (p=0.013). Nevertheless, the presence of TP53 mutation could stratify the PFS and OS of patients with IDH1 wild type (p=0.003 and 0.029 respectively, log-rank). The MGMT promoter methylation and TP53 mutation were associated with a favorable outcome of patients with and without mutant IDH1, respectively. The results indicate that glioblastomas with MGMT methylation or TP53 mutations have improved survival that may be influenced by IDH1 mutation status.

TP53 Mutation Is a Prognostic Factor in Lower Grade Glioma and May Influence Chemotherapy Efficacy

“…Survival analysis of the TCGA astrocytoma dataset confirmed our findings. In LGG, this is the first report of TP53 mutation being a favourable prognostic factor, although this was reported previously in other cancers, including glioblastoma [93,94], sarcomas [95], ovarian serous cystadenocarcinoma [96] and cervical cancer [97]. In multivariate analysis adjusting for IDH1 mutation, age, gender and tumour grade, the combined TP53 mutation showed a trend for improved survival compared to WT, leading us to believe there are specific TP53 mutations accounting for the improved survival in the univariate analysis.…”

Associations among smoking, MGMT hypermethylation, TP53-mutations, and relapse in head and neck squamous cell carcinoma

“…The expressions of MGMT RNA and protein are decreased by methylation of a CpG island in its promoter region [7,8]. Thus, aberrant hypermethylation of the MGMT promoter region (hmMGMT) may hamper its DNA repair function, allowing mutations of G:C>A:T transition in TP53, as well as other carcinogenic genes, in various cancers [9][10][11][12].…”

Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature

“…1 C). Recently, it was reported that TP53 mutation status alone is associated with improved survival in glioblastoma 27 . Our results support this observation.…”