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Erschienen in: Acta Neuropathologica 3/2017

27.01.2017 | Original Paper

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

verfasst von: Adriana Olar, Khalida M. Wani, Charmaine D. Wilson, Gelareh Zadeh, Franco DeMonte, David T. W. Jones, Stefan M. Pfister, Erik P. Sulman, Kenneth D. Aldape

Erschienen in: Acta Neuropathologica | Ausgabe 3/2017

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Abstract

Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n = 140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n = 89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNAs)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p = 0.0793). The methylation predictor, however, was significantly associated with tumor recurrence (p < 0.0001). CNAs were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.
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Metadaten
Titel
Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma
verfasst von
Adriana Olar
Khalida M. Wani
Charmaine D. Wilson
Gelareh Zadeh
Franco DeMonte
David T. W. Jones
Stefan M. Pfister
Erik P. Sulman
Kenneth D. Aldape
Publikationsdatum
27.01.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Acta Neuropathologica / Ausgabe 3/2017
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1678-x

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