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  • 1
    Abstract: OBJECTIVE Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade. METHODS Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed. RESULTS TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses. CONCLUSIONS Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.
    Type of Publication: Journal article published
    PubMed ID: 28621624
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  • 2
    Publication Date: 2013-01-26
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clark, Victoria E -- Erson-Omay, E Zeynep -- Serin, Akdes -- Yin, Jun -- Cotney, Justin -- Ozduman, Koray -- Avsar, Timucin -- Li, Jie -- Murray, Phillip B -- Henegariu, Octavian -- Yilmaz, Saliha -- Gunel, Jennifer Moliterno -- Carrion-Grant, Geneive -- Yilmaz, Baran -- Grady, Conor -- Tanrikulu, Bahattin -- Bakircioglu, Mehmet -- Kaymakcalan, Hande -- Caglayan, Ahmet Okay -- Sencar, Leman -- Ceyhun, Emre -- Atik, A Fatih -- Bayri, Yasar -- Bai, Hanwen -- Kolb, Luis E -- Hebert, Ryan M -- Omay, S Bulent -- Mishra-Gorur, Ketu -- Choi, Murim -- Overton, John D -- Holland, Eric C -- Mane, Shrikant -- State, Matthew W -- Bilguvar, Kaya -- Baehring, Joachim M -- Gutin, Philip H -- Piepmeier, Joseph M -- Vortmeyer, Alexander -- Brennan, Cameron W -- Pamir, M Necmettin -- Kilic, Turker -- Lifton, Richard P -- Noonan, James P -- Yasuno, Katsuhito -- Gunel, Murat -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32GM07205/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1077-80. doi: 10.1126/science.1233009. Epub 2013 Jan 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23348505" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/classification/*genetics/pathology ; Chromosomes, Human, Pair 22/genetics ; DNA Mutational Analysis ; Female ; Genes, Neurofibromatosis 2 ; Genomic Instability ; Genomics ; Humans ; Kruppel-Like Transcription Factors/*genetics ; Male ; Meningeal Neoplasms/classification/*genetics/pathology ; Meningioma/classification/*genetics/pathology ; Middle Aged ; Mutation ; Neoplasm Grading ; Proto-Oncogene Proteins c-akt/*genetics ; Receptors, G-Protein-Coupled/*genetics ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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