Dual MGMT inactivation by promoter hypermethylation and loss of the long arm of chromosome 10 in glioblastoma.

Background Epigenetic inactivation of O6-methylguanine-methyltransferase (MGMT) gene by methylation of its promoter is predictive of Temozolomid (TMZ) response in glioblastoma (GBM).MGMTis located on chromosome 10q26 and the loss of chromosome 10q is observed in 70% of GBMs. In this study, we assessed the hypothesis that the dual inactivation ofMGMT, by hypermethylation ofMGMTpromoter and by loss the long arm of chromosome 10 (10q), may confer greater sensitivity to TMZ. Methods A total of 149 tumor samples from patients diagnosed with GBM based on the WHO 2016 classification were included in this retrospective study between November 2016 and December 2018. Methylation status ofMGMTpromoter was evaluated by pyrosequencing and status of chromosome 10q was assessed by array comparative genomic hybridization. Results Glioblastoma patients with chromosome 10q loss associated with hypermethylation ofMGMTpromoter had significantly longer overall survival (OS) (P = .0024) and progression-free survival (PFS) (P = .031). Indeed, median OS of patients with dual inactivation ofMGMTwas 21.5 months compared to 12 months and 8.1 months for groups with singleMGMTinactivation by hypermethylation and by 10q loss, respectively. The group with noMGMTinactivation had 9.5 months OS. Moreover, all long-term survivors with persistent response to TMZ treatment (OS >= 30 months) displayed dual inactivation ofMGMT. Conclusions Our data suggest that the molecular subgroup characterized by the dual inactivation ofMGMTreceives greater benefit from TMZ treatment. The results of our study may be of immediate clinical interest since chromosome 10q status and methylation ofMGMTpromoter are commonly determined in routine practice.