Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation

Abstract

The high level of methylguanine-DNA methyltransferase (MGMT) in glioblastoma is responsible for resistance to alkylating agents, such as temozolomide (TMZ). In glioblastomas with a methylated MGMT promoter, MGMT deficiency is presumed, resulting in an enhanced effect of TMZ. The aim of the present study was to investigate whether genomic alterations work synergistically with MGMT methylation status and contribute to the response to treatment and overall prognosis in glioblastoma. The current study included a cohort of 35 glioblastoma patients, with MGMT promoter methylation present in 48% of tumors. MGMT methylation was associated with significantly longer median survival (29.0 months) compared with patients without MGMT methylated tumors (12.0 months), as well as longer median time to progression following TMZ treatment (13.2 months, compared with 5.6 months for patients with an unmethylated MGMT status). In addition, somatic variants in hot spot exonic regions of 50 key cancer genes were examined in these glioblastomas. Non-synonymous mutations in methylated MGMT glioblastomas were four times higher compared with unmethylated MGMT glioblastomas. Furthermore, significantly increased frequencies of mutations in the TP53, CDKN2A, PTEN and PIK3CA genes were detected in MGMT methylated glioblastomas. The relative significance of these mutations, and their contribution to TMZ sensitivity, adjunct to MGMT methylation, require further investigation in a larger cohort.

Keywords: glioblastoma; methylguanine-DNA methyltransferase methylation; mutations.

Figure 1.

Kaplan-Meier survival curves based on (A) TTP and (B) overall survival for glioblastoma patients stratified by MGMT methylation. Results of log-rank tests and the median survival for each group is provided. MGMT, methylguanine-DNA methyltransferase; TTP, time-to-progression.

Figure 2.

Overall gene alteration patterns for 11 target genes in 33 samples. Blue bars represent single nucleotide polymorphisms, red bars represent amplification, yellow bars represent deletions, grey bars represent MGMT methylation and black bars represent MGMT unmethylation. Numbers inside the bars show the alteration number. Sample number (no.), age (years) and OS (months) are also provided. MGMT, methylguanine-DNA methyltransferase; OS, overall survival.