title: Alterations of the RRAS and ERCC1 genes at 19q13 in gemistocytic astrocytomas.
abstract: Gemistocytic astrocytoma (World Health Organization grade II) is a rare variant of diffuse astrocytoma that is characterized by the presence of neoplastic gemistocytes and has a significantly less favorable prognosis. Other than frequent TP53 mutations (>80%), little is known about its molecular profile. Here, we show that gemistocytic astrocytomas carry a lower frequency of IDH mutations than fibrillary astrocytomas (74% vs 92%; p = 0.0255) but have profiles similar to those of fibrillary astrocytomas with respect to TERT promoter mutations (5% vs 0%), 1p/19q loss (10% vs 8%), and loss of heterozygosity 10q (10% vs 12%). Exome sequencing in 5 gemistocytic astrocytomas revealed homozygous deletion of genes at 19q13 (i.e. RRAS [related RAS viral oncogene homolog; 2 cases] and ERCC1 [excision repair cross-complementing rodent repair deficiency, complementation group 1; 1 case]). Further screening showed RRAS homozygous deletion in 7 of 42 (17%) gemistocytic astrocytomas and in 3 of 24 (13%) IDH1 mutated secondary glioblastomas. Patients with gemistocytic astrocytoma and secondary glioblastoma with an RRAS deletion tended to have shorter survival rates than those without deletion. Differential polymerase chain reaction and methylation-specific polymerase chain reaction revealed an ERCC1 homozygous deletion or promoter methylation in 10 of 42 (24%) gemistocytic astrocytomas and in 8 of 24 (33%) secondary glioblastomas. Alterations in RRAS and ERCC1 appear to be typical in gemistocytic astrocytomas and secondary glioblastomas, since they were not present in 49 fibrillary astrocytomas or 30 primary glioblastomas.
authors.affiliation: From the International Agency for Research on Cancer (TO, YHK, JEO, KS, NNo, HO); ProfileXpert, SFR Santé Lyon-Est UCBL UMS 3453 CNRS-US7 (NNa, FB, JL); and Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286 (JL), INSERM, Lyon; and CNRS UMR 5293, Bordeaux (AV), France; Translational Epidemiology Research Branch, National Cancer Center, Goyang, Republic of Korea (YHK); Institute of Neuropathology, University Hospital Munster, Munster (WP); Institute of Neuropathology (KK) and Department of Neurosurgery (DP, US), University Hospital Essen, Essen; and Institute of Neurology (Edinger Institute), Goethe-University Frankfurt, Frankfurt (MM), Germany; Department of Human Pathology, Gunma University, Maebashi, Japan (HY); Cure Brain Cancer Neuro-oncology Group, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia (KM, PK); and Medical Faculty, University Zurich, Zurich, Switzerland (PK).
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohta
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Oh
authors.forename: Kaishi
authors.initials: K
authors.lastname: Satomi
authors.forename: Naosuke
authors.initials: N
authors.lastname: Nonoguchi
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.forename: Daniela
authors.initials: D
authors.lastname: Pierscianek
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Kerrie
authors.initials: K
authors.lastname: McDonald
authors.forename: Paul
authors.initials: P
authors.lastname: Kleihues
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nazaret
authors.forename: Fabienne
authors.initials: F
authors.lastname: Barbet
authors.forename: Joel
authors.initials: J
authors.lastname: Lachuer
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D001254:Astrocytoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D015996:Survival Rate / Q000639:trends; D018631:ras Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; C085929:RRAS protein, human; D018631:ras Proteins