CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas

Sievers, Philipp; Hielscher, Thomas; Schrimpf, Daniel; Stichel, Damian; Reuß, David; Berghoff, Anna Sophie; Neidert, Marian C.; Wirsching, Hans-Georg; Mawrin, Christian; Ketter, Ralf; Paulus, Werner; Reifenberger, Guido; Lamszus, Katrin; Westphal, Manfred; Etminan, Nima; Ratliff, Miriam; Herold‐Mende, Christel; Pfister, Stefan M.; Jones, David; Weller, Michael; Harter, Patrick N.; Wick, Wolfgang; Preusser, Matthias; Deimling, Andreas von; Sahm, Felix

doi:10.1007/s00401-020-02188-w

Cited by 129 publications

(90 citation statements)

References 12 publications

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“… 5 With the description of the negative prognostic impact of TERT promoter mutations and CDKN2A/B deletions, the integration of molecular markers into the risk stratification of meningiomas has been suggested. 6 , 7 , 15 Furthermore, the use of DNA methylation profiling for improved prognostication in meningioma has been advocated. 16 , 17 The role of histone modifications in cancer has gained increasing attention in the last decade 18 and new insights were also reported in the field of neuro-oncology with the detection of alterations of histone demethylases in meningiomas.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular markers such as the telomerase reverse transcriptase (TERT) promotor and loss of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) are prognostically relevant but only present in a small subset of (mostly anaplastic) meningiomas. 6 , 7 Therefore, further strengthening of prognostication is necessary to provide clinicians and their patients with information on the expected disease course.…”

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confidence: 99%

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H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort

et al. 2020

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Background A loss of the trimethylation of lysine 27 of histone H3 (H3K27me3) in meningioma has been recently suggested as an adjunct to identify subsets of higher risk of recurrence. The aim of the present study was to assess the prognostic value of H3K27 histone trimethylation and its potential clinical utility in the “Tübingen meningioma cohort”. Methods Patients who underwent meningioma resection between 10/2003 and 1/22015 at the University Hospital Tübingen were included. Immunohistochemical stainings for H3K27me3 and the proliferation marker MIB1 were assessed and correlated with clinical parameters using univariate and multivariate cox regressions as well as Pearson’s chi-squared and log-rank test. Results Overall, 1268 meningiomas were analyzed with a female to male ratio of 2.6 and a mean age of 58.7 years (range 8.3 – 91.0). With 163 cases lost to follow up, 1103 cases were available for further analysis with a mean follow-up of 40.3 months (range 1.1 – 186.3). Male gender, younger age, intracranial tumor localization, progressive tumor, subtotal resection, higher WHO grade, increased MIB1 rate and loss of H3K27me3 were significant negative prognostic factors in the univariate analysis. H3K27me3 status and all other prognostic factors, except age and tumor location, remained significant in the multivariate model. Furthermore, adjuvant radiotherapy was an independent positive prognostic factor. Conclusions Loss of H3K27me3 combined with MIB1 labeling index are independent prognostic factors in meningioma. These data from the Tübingen meningioma cohort support the clinical utility of H3K27me3 immunohistochemical staining in meningioma and its integration into the routine histopathological workup.

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Section: Discussionmentioning

confidence: 99%

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H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort

et al. 2020

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“…On a molecular level, tumors can be roughly dichotomized as NF2 (neurofibromatosis type 2) and non-NF2-mutated meningiomas, and NF2 is the main identified driver mutation in atypical meningiomas [9,10]. Mutations of the promotor of the telomere reverse transcriptase (TERT), loss of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and loss of the trimethylation of lysin 27 of histone 3 (H3K27me3), were identified as negative prognostic markers independent of tumor histology [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Brain Invasion in Meningioma—A Prognostic Potential Worth Exploring

Behling

Hempel

Schittenhelm

2021

Cancers

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Most meningiomas are slow growing tumors arising from the arachnoid cap cells and can be cured by surgical resection or radiation therapy in selected cases. However, recurrent and aggressive cases are also quite common and challenging to treat due to no established treatment alternatives. Assessment of the risk of recurrence is therefore of utmost importance and several prognostic clinical and molecular markers have been established. Additionally, the identification of invasive growth of meningioma cells into CNS tissue was demonstrated to lead to a higher risk of recurrence and was therefore integrated into the WHO classification of CNS tumors. However, the evidence for its prognostic impact has been questioned in subsequent studies and its exclusion from the next WHO classification proposed. We were recently able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. In this review we discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor.

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“…In addition, several mutations have been described with potential prognostic implications in HGMs (12,14,18). Data published recently have also shown that activating TERT promoter mutations, frequent inactivation of BAP1, deletions of CDKN2A/ B, and mutations in DMD are frequent in meningiomas with malignant histological progression (18)(19)(20)(21). These data suggest that convergent gene-expression programs may underlie HGMs, which could be leveraged to develop prognostic biomarkers.…”

Section: Introductionmentioning

confidence: 85%

“…Tumor genotyping was performed on formalin-fixed paraffinembedded (FFPE) tumor tissue by next-generation sequencing (NGS) covering 184 genes, including common pathological relevant genes of meningiomas (Supplementary Table S2) (13)(14)(15)(16)(17)(18)(19)(20)(21)23). Five DNA samples were excluded for sequencing due to inadequate quality of concentration.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

TERT Alterations Predict Tumor Progression in De Novo High-Grade Meningiomas Following Adjuvant Radiotherapy

et al. 2021

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BackgroundAdjuvant radiotherapy (RT) is one of the most commonly used treatments for de novo high-grade meningiomas (HGMs) after surgery, but genetic determinants of clinical benefit are poorly characterized.ObjectiveWe describe efforts to integrate clinical genomics to discover predictive biomarkers that would inform adjuvant treatment decisions in de novo HGMs.MethodsWe undertook a retrospective analysis of 37 patients with de novo HGMs following RT. Clinical hybrid capture-based sequencing assay covering 184 genes was performed in all cases. Associations between tumor clinical/genomic characteristics and RT response were assessed. Overall survival (OS) and progression-free survival (PFS) curves were plotted using the Kaplan–Meier method.ResultsAmong the 172 HGMs from a single institution, 42 cases (37 WHO grade 2 meningiomas and five WHO grade 3 meningiomas) were identified as de novo HGMs following RT. Only TERT mutations [62.5% C228T; 25% C250T; 12.5% copy number amplification (CN amp.)] were significantly associated with tumor progression after postoperative RT (adjusted p = 0.003). Potential different somatic interactions between TERT and other tested genes were not identified. Furthermore, TERT alterations (TERT-alt) were the predictor of tumor progression (Fisher’s exact tests, p = 0.003) and were associated with decreased PFS (log-rank test, p = 0.0114) in de novo HGMs after RT.ConclusionOur findings suggest that TERT-alt is associated with tumor progression and poor outcome of newly diagnosed HGM patients after postoperative RT.

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CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas

Cited by 129 publications

References 12 publications

H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort

H3K27me3 loss indicates an increased risk of recurrence in the Tübingen meningioma cohort

Brain Invasion in Meningioma—A Prognostic Potential Worth Exploring

TERT Alterations Predict Tumor Progression in De Novo High-Grade Meningiomas Following Adjuvant Radiotherapy

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