title: Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations.
abstract: Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Liu
authors.forename: Noha
authors.initials: N
authors.lastname: Gerges
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.forename: Dong-Anh
authors.initials: DA
authors.lastname: Khuong-Quang
authors.forename: Adam M
authors.initials: AM
authors.lastname: Fontebasso
authors.forename: Adam
authors.initials: A
authors.lastname: Fleming
authors.forename: Djihad
authors.initials: D
authors.lastname: Hadjadj
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.forename: Peter
authors.initials: P
authors.lastname: Siegel
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Martje
authors.initials: M
authors.lastname: Tonjes
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Damien
authors.initials: D
authors.lastname: Faury
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
mesh_terms: D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000075924:X-linked Nuclear Protein; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein