Posttreatment Effect of MGMT Methylation Level on Glioblastoma Survival

Rikke H Dahlrot, Pia Larsen, Henning B Boldt, Melissa S Kreutzfeldt, Steinbjørn Hansen, Jacob B Hjelmborg, Bjarne Winther Kristensen

Abstract

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes temozolomide-induced alkylation, thereby preventing DNA damage and cytotoxicity. We investigated the prognostic effect of different MGMT methylation levels on overall and progression-free survival in 327 patients with primary glioblastoma undergoing standard treatment. We obtained MGMT methylation level in 4 CpG sites using pyrosequencing. The association between MGMT methylation level and survival was investigated using Cox proportional hazards model and an extension to detect time-varying effects. We found an association between MGMT methylation level and overall survival (OS) from around 9 months after the diagnosis, with no association between MGMT methylation level and OS before that. For patients surviving at least 9 months even small increases in MGMT methylation level are significantly beneficial (HR = 0.97, 95% CI [0.96, 0.98]). The predictive ability of MGMT methylation level on OS from 9 months after diagnosis has a Harrel's C of 66%. We conclude that the MGMT methylation level is strongly associated with survival only for patients surviving beyond 9 months with considerable effects for levels much lower than previously reported. Prognostic evaluation of cut-points of MGMT methylation levels and of CpG island site selection should take the time-varying effect on overall survival into account.

OriginalsprogEngelsk
TidsskriftJournal of Neuropathology and Experimental Neurology
Vol/bind78
Udgave nummer7
Sider (fra-til)633-640
Antal sider8
ISSN0022-3069
DOI
StatusUdgivet - 1 jul. 2019
Udgivet eksterntJa

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