title: IDH mutation is associated with higher risk of malignant transformation in low-grade glioma.
abstract: Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR(DEATH) = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR(MT) = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR(DEATH) versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR(MT) versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.
authors.affiliation: Neurosurgery Clinic, University Hospital Basel, Basel, Switzerland.
authors.forename: Severina
authors.initials: S
authors.lastname: Leu
authors.affiliation: Clinical Trial Unit, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: von Felten
authors.affiliation: Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.affiliation: Laboratory of Brain Tumor Biology, Department of Biomedicine, University Hospital Basel, Room 7009, PharmaCenter, Klingelbergstrasse 50-70, 4056, Basel, Switzerland. jean-louis.boulay@unibas.ch.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Boulay
authors.affiliation: Laboratory of Brain Tumor Biology, Department of Biomedicine, University Hospital Basel, Room 7009, PharmaCenter, Klingelbergstrasse 50-70, 4056, Basel, Switzerland.|Neurosurgery Clinic, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Biomarker; Brain tumor; Gliomagenesis; MGMT; Survival