title: 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 methylatedMGMTpromoter, 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 withMGMTmethylation status and contribute to the response to treatment and overall prognosis in glioblastoma. The current study included a cohort of 35 glioblastoma patients, withMGMTpromoter methylation present in 48% of tumors.MGMTmethylation was associated with significantly longer median survival (29.0 months) compared with patients withoutMGMTmethylated 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 unmethylatedMGMTstatus). In addition, somatic variants in hot spot exonic regions of 50 key cancer genes were examined in these glioblastomas. Non-synonymous mutations in methylatedMGMTglioblastomas were four times higher compared with unmethylatedMGMTglioblastomas. Furthermore, significantly increased frequencies of mutations in theTP53,CDKN2A,PTENandPIK3CAgenes were detected inMGMTmethylated glioblastomas. The relative significance of these mutations, and their contribution to TMZ sensitivity, adjunct toMGMTmethylation, require further investigation in a larger cohort.
authors.affiliation: Cure Brain Cancer Neuro-oncology Group, Prince of Wales Clinical School, Lowy Cancer Research Centre C25, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley WA 6009, Australia.
authors.forename: Tania
authors.initials: T
authors.lastname: Tabone
authors.affiliation: Harry Perkins Institute of Medical Research, Nedlands WA 6009, Australia.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley WA 6009, Australia.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
keywords: glioblastoma; methylguanine-DNA methyltransferase methylation; mutations