Adult intracranial ependymoma—relevance of DNA methylation profiling for diagnosis, prognosis, and treatment

Abstract

Background A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Methods Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from eight diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). Results The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6% and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (p=0.009) and postoperative radiotherapy (p=0.007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of prognosis within molecularly defined ependymoma classes. Conclusions DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. Gross total resection and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas

“…While this did not impair the OS of the affected patients, it does not fit the view of these tumors as rather non-aggressive entities. We were thus able to support similar results of previous analyses focused on these molecular classes [ 3 , 39 , 40 ]. For the EPN-PFA subtypes, the separation between the groups PFA-1 and PFA-2 was possible, but the separation between the smaller molecular subtypes was not as clear, both in the analysis of all samples and when restricted to EPN-PFA tumors only.…”

“…For these samples, the class with the highest score in the Heidelberg brain tumor classifier v12b6 was a molecular type of ependymoma [ 5 ]. For previously published samples, the raw methylation values and clinical data were collected from Gene Expression Omnibus and the corresponding authors (GSE65362, GSE104210, GSE117130, GSE109379, GSE90496, GSE114523, GSE169265, GSE224218, GSE182707, GSE184900, GSE196013, GSE215240) [ 3 , 5 , 7 , 11 , 29 , 30 , 32 , 36 , 38 – 40 ]. Multiple samples of the same patient were identified via SNP analysis, and only one sample was included in our analyses.…”

Clinical impact of molecular profiling in rare brain tumors

“…Examples include astroblastoma, an uncommon neuroepithelial tumor associated with an MN1 gene fusion, and BCOR -altered CNS tumors. Indeed, a recent study of 170 adult patients diagnosed with grade 2 and 3 intracranial ependymoma illustrated the improved risk stratification with molecular classification of ependymal tumors, showing only 73.5% of cases were correctly classified as ependymoma [47].…”

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors

“…This approach has been very fruitful both for research and daily diagnostic purposes. Concerning the first aim, many novel tumor types and subtypes have been discovered or comprehensively characterized thanks to the unsupervised analysis of large datasets of brain tumors [7][8][9][10][11][12]. Many of the newly identified tumors show significant overlaps with other entities in terms of morphological features and/or a very low incidence, contributing to explain why they were previously unrecognized as distinct neoplasms by conventional light microscopy.…”