Intrinsic glioma subtypes in EORTC 26951
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Pim French
PROVIDER: E-GEOD-43388 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.
Mack S C SC Witt H H Piro R M RM Gu L L Zuyderduyn S S Stütz A M AM Wang X X Wang X X Gallo M M Garzia L L Zayne K K Zhang X X Ramaswamy V V Jäger N N Jones D T W DT Sill M M Pugh T J TJ Ryzhova M M Wani K M KM Shih D J H DJ Head R R Remke M M Bailey S D SD Zichner T T Faria C C CC Barszczyk M M Stark S S Seker-Cin H H Hutter S S Johann P P Bender S S Hovestadt V V Tzaridis T T Dubuc A M AM Northcott P A PA Peacock J J Bertrand K C KC Agnihotri S S Cavalli F M G FM Clarke I I Nethery-Brokx K K Creasy C L CL Verma S K SK Koster J J Wu X X Yao Y Y Milde T T Sin-Chan P P Zuccaro J J Lau L L Pereira S S Castelo-Branco P P Hirst M M Marra M A MA Roberts S S SS Fults D D Massimi L L Cho Y J YJ Van Meter T T Grajkowska W W Lach B B Kulozik A E AE von Deimling A A Witt O O Scherer S W SW Fan X X Muraszko K M KM Kool M M Pomeroy S L SL Gupta N N Phillips J J Huang A A Tabori U U Hawkins C C Malkin D D Kongkham P N PN Weiss W A WA Jabado N N Rutka J T JT Bouffet E E Korbel J O JO Lupien M M Aldape K D KD Bader G D GD Eils R R Lichter P P Dirks P B PB Pfister S M SM Korshunov A A Taylor M D MD
Nature 20140219 7489
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants ...[more]
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Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
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