title: The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.
abstract: Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ.
authors.affiliation: INSERM-U1103 and.|CNRS-UMR 6293, Clermont-Ferrand 63001, France.|GReD Laboratory, Clermont Auvergne University, Clermont-Ferrand 63000, France.|Biochemistry and Molecular Biology Department, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fogli
authors.affiliation: Clermont Auvergne University, EA 7283 CREaT, Clermont-Ferrand 63000, France.|Radiotherapy Department, Jean Perrin Center, Clermont-Ferrand 63011, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chautard
authors.affiliation: INSERM-U1103 and.|CNRS-UMR 6293, Clermont-Ferrand 63001, France.|GReD Laboratory, Clermont Auvergne University, Clermont-Ferrand 63000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vaurs-Barrière
authors.affiliation: Biostatistics Department , DRCI, Clermont-Ferrand Hospital , Clermont-Ferrand 63003 , France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pereira
authors.affiliation: Clermont Auvergne University , EA 7283 CREaT, Clermont-Ferrand 63000 , France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Müller-Barthélémy
authors.affiliation: INSERM-U1103 and.|CNRS-UMR 6293, Clermont-Ferrand 63001, France.|GReD Laboratory, Clermont Auvergne University, Clermont-Ferrand 63000, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Court
authors.affiliation: Clermont Auvergne University, EA 7283 CREaT, Clermont-Ferrand 63000, France.|Radiotherapy Department, Jean Perrin Center, Clermont-Ferrand 63011, France.
authors.forename: Julian
authors.initials: J
authors.lastname: Biau
authors.affiliation: Department of Neurosurgery , Braga Hospital , Braga 4710-243 São Victor , Portugal.
authors.forename: Afonso Almeida
authors.initials: AA
authors.lastname: Pinto
authors.affiliation: Department of Anatomopathology , Clermont-Ferrand Hospital , Clermont-Ferrand 63003 , France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kémény
authors.affiliation: Department of Neurosurgery, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France.|Clermont Auvergne University, EA 7282 IGCNC, Clermont-Ferrand 63000, France.
authors.forename: Toufic
authors.initials: T
authors.lastname: Khalil
authors.affiliation: INSERM-U935, Poitiers 86021, France.|Poitiers University, Poitiers 86000, France.|Cancer Biology Laboratory, Poitiers Hospital, Poitiers 86021, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Karayan-Tapon
authors.affiliation: Clermont Auvergne University, EA 7283 CREaT, Clermont-Ferrand 63000, France.|Radiotherapy Department, Jean Perrin Center, Clermont-Ferrand 63011, France.|INSERM U2021 CNRS UMR3347, Curie Institute, Orsay 91405, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verrelle
authors.affiliation: School of Health Sciences, Life and Health Sciences Research Institute (ICVS), Braga 4710-057, Portugal and.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Braga 4710-057, Portugal.
authors.forename: Bruno Marques
authors.initials: BM
authors.lastname: Costa
authors.affiliation: INSERM-U1103 and.|CNRS-UMR 6293, Clermont-Ferrand 63001, France.|GReD Laboratory, Clermont Auvergne University, Clermont-Ferrand 63000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005838:Genotype; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes