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Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

ABSTRACT: Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.

SUBMITTER: Witt H

PROVIDER: S-EPMC4154494 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

Witt Hendrik H Mack Stephen C SC Ryzhova Marina M Bender Sebastian S Sill Martin M Isserlin Ruth R Benner Axel A Hielscher Thomas T Milde Till T Remke Marc M Jones David T W DT Northcott Paul A PA Garzia Livia L Bertrand Kelsey C KC Wittmann Andrea A Yao Yuan Y Roberts Stephen S SS Massimi Luca L Van Meter Tim T Weiss William A WA Gupta Nalin N Grajkowska Wiesia W Lach Boleslaw B Cho Yoon-Jae YJ von Deimling Andreas A Kulozik Andreas E AE Witt Olaf O Bader Gary D GD Hawkins Cynthia E CE Tabori Uri U Guha Abhijit A Rutka James T JT Lichter Peter P Korshunov Andrey A Taylor Michael D MD Pfister Stefan M SM

Cancer cell 20110801 2

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are mu ...[more]

PMID: 21840481

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Project description:BackgroundPosterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years.MethodsDemographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3).ResultsA total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042).ConclusionsData from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

Dataset Information

Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

Publications

Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

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