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 <i>MGMT</i> 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 <i>MGMT</i> 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 <i>MGMT</i> promoter methylation present in 48% of tumors. <i>MGMT</i> methylation was associated with significantly longer median survival (29.0 months) compared with patients without <i>MGMT</i> 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 <i>MGMT</i> 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 <i>MGMT</i> glioblastomas were four times higher compared with unmethylated <i>MGMT</i> glioblastomas. Furthermore, significantly increased frequencies of mutations in the <i>TP53</i>, <i>CDKN2A</i>, <i>PTEN</i> and <i>PIK3CA</i> genes were detected in <i>MGMT</i> methylated glioblastomas. The relative significance of these mutations, and their contribution to TMZ sensitivity, adjunct to <i>MGMT</i> methylation, require further investigation in a larger cohort.