title: Alterations in the RB1 pathway in low-grade diffuse gliomas lacking common genetic alterations.
abstract: We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14(ARF) , p15(INK4b) , p16(INK4a)  loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15(INK4b) , p16(INK4a)  and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Joel
authors.initials: J
authors.lastname: Lachuer
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brokinkel
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Karsten
authors.initials: K
authors.lastname: Wrede
authors.forename: Sumihito
authors.initials: S
authors.lastname: Nobusawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D019942:Genes, p16; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D055815:Young Adult
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D016160:Retinoblastoma Protein