title: Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951.
abstract: Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology.
authors.affiliation: Department of Neurology, Daniel den Hoed Cancer Center, Erasmus University Hospital, Rotterdam, The Netherlands.
authors.forename: Mathilde C M
authors.initials: MC
authors.lastname: Kouwenhoven
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibdaih
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.forename: Jacolien E C
authors.initials: JE
authors.lastname: Bromberg
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: van Duinen
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Teepen
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Fanny
authors.initials: F
authors.lastname: Vandenbos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Grisold
authors.forename: László
authors.initials: L
authors.lastname: Sipos
authors.forename: Rene
authors.initials: R
authors.lastname: Mirimanoff
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Vecht
authors.forename: Anouk
authors.initials: A
authors.lastname: Allgeier
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001254:Astrocytoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017326:Clinical Trials, Phase III as Topic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008130:Lomustine / Q000008:administration & dosage; D009336:Necrosis; D009367:Neoplasm Staging; D009837:Oligodendroglioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011344:Procarbazine / Q000008:administration & dosage; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine