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      DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

      1 , 2 , 2 , 1 , 2 , 2 , 2 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 5 , 15 , 15 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 1 , 2 , 16 , 1 , 2 , 17 , International Consortium on Meningiomas

      Neuro-Oncology

      Oxford University Press (OUP)

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          Abstract

          Background

          Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.

          Methods

          DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.

          Results

          The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications.

          Conclusions

          The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

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          Most cited references 16

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          Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

          We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
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            Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

            Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas 1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
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              Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review.

              Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma.
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                Author and article information

                Journal
                Neuro-Oncology
                Oxford University Press (OUP)
                1522-8517
                1523-5866
                July 2019
                July 11 2019
                June 03 2019
                July 2019
                July 11 2019
                June 03 2019
                : 21
                : 7
                : 901-910
                Affiliations
                [1 ]Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
                [2 ]MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
                [3 ]Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
                [4 ]Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA
                [5 ]Interdisciplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research & Center for CNS Tumors, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany
                [6 ]Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany
                [7 ]Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
                [8 ]Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA
                [9 ]Edinger Institute (Institute of Neurology), Goethe-University, Frankfurt am Main, Germany
                [10 ]Department of Neurosurgery, Goethe-University, Frankfurt am Main, Germany
                [11 ]Department of Neurology, University Hospital Zurich, Zurich, Switzerland
                [12 ]Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center CNS Unit, Medical University of Vienna, Vienna, Austria
                [13 ]Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
                [14 ]Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany
                [15 ]Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
                [16 ]Division of Neurosurgery, University Health Network, Toronto, Ontario, Canada
                [17 ]Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
                Article
                10.1093/neuonc/noz061
                6620635
                31158293
                © 2019

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