title: Epigenetic silencing of XAF1 in high-grade gliomas is associated with IDH1 status and improved clinical outcome.
abstract: XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a tumor suppressor that counteracts the anti-apoptotic effects of XIAP and can sensitize cells to cell death triggering events. XAF1 knockdown abrogated the temozolomide (TMZ)-induced G2-arrest and prevented TMZ-induced apoptosis in the glioblastoma (GB) cell line LN229. Promoter methylation of XAF1 was found to be inversely correlated with mRNA expression in GB cells. We analyzed XAF1 methylation in a panel of 16 GB cell lines and 80 patients with first-diagnosed WHO grade III/IV high-grade gliomas using methylation-sensitive high-resolution melt (MS-HRM) analysis. In those patients, XAF1 promoter methylation was strongly associated with enhanced progression free and overall survival. Interestingly, XAF1 promoter methylation was strictly correlated with the occurrence of IDH1 mutations, indicating a causal link to the IDH1 mutant phenotype. XAF1 methylation was observed in 18 grade III tumors all of which showed heterozygous mutations in the IDH1 gene. 17 harbored a mutation leading to an arginine > histidine (R132H) and one carried a mutation causing an arginine > glycine (R132G) substitution. Furthermore, six out of six recurrent and IDH1 mutated grade III tumors also showed XAF1 promoter methylation. The data demonstrate that XAF1 promoter methylation determined by MS-HRM is a robust and precise indicator of IDH1 mutations in grade III gliomas. It is useful for complementing the immunohistochemistry-based detection of mutant IDH, uncovering rare 2-HG-producing IDH1 and potentially IDH2 mutations. The MS-HRM-based detection of XAF1 methylation could therefore be a reliable tool in assisting the sub-classification of high-grade gliomas.
authors.affiliation: Department of Toxicology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Reich
authors.affiliation: Department of Toxicology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Switzeny
authors.affiliation: Department of Neurosurgery, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Renovanz
authors.affiliation: Department of Neuropathology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Department of Toxicology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.affiliation: Department of Toxicology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Christmann
authors.affiliation: Department of Toxicology, University Medical Center, D-55131 Mainz, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Tomicic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C417551:XAF1 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: IDH1; XAF1 promoter methylation; glioblastoma; high-grade glioma; temozolomide