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

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 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 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 promoter methylation present in 48% of tumors. methylation was associated with significantly longer median survival (29.0 months) compared with patients without 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 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 glioblastomas were four times higher compared with unmethylated glioblastomas. Furthermore, significantly increased frequencies of mutations in the , , and genes were detected in methylated glioblastomas. The relative significance of these mutations, and their contribution to TMZ sensitivity, adjunct to methylation, require further investigation in a larger cohort.