Browsing by Author "Murray, Phillip B."

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    Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO
    (AMER ASSOC ADVANCEMENT SCIENCE, 2013-01-01) Clark, Victoria E.; Erson-Omay, E. Zeynep; Serin, Akdes; Yin, Jun; Cotney, Justin; Oezduman, Koray; Avsar, Timuin; Li, Jie; Murray, Phillip B.; Henegariu, Octavian; Yilmaz, Saliha; Guenel, 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.; Bilguevar, Kaya; Baehring, Joachim M.; Gutin, Philip H.; Piepmeier, Joseph M.; Vortmeyer, Alexander; Brennan, Cameron W.; Pamir, M. Necmettin; Kilic, Tuerker; Lifton, Richard P.; Noonan, James P.; Yasuno, Katsuhito; Guenel, Murat
    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 similar to 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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    Integrated genomic characterization of IDH1-mutant glioma malignant progression
    (NATURE PUBLISHING GROUP, 2016-01-01) Bai, Hanwen; Harmanci, Akdes Serin; Erson-Omay, E. Zeynep; Li, Jie; Coskun, Sueleyman; Simon, Matthias; Krischek, Boris; Ozduman, Koray; Omay, S. Buelent; Sorensen, Eric A.; Turcan, Sevin; Bakirciglu, Mehmet; Carrion-Grant, Geneive; Murray, Phillip B.; Clark, Victoria E.; Ercan-Sencicek, A. Gulhan; Knight, James; Sencar, Leman; Altinok, Selin; Kaulen, Leon D.; Guelez, Burcu; Timmer, Marco; Schramm, Johannes; Mishra-Gorur, Ketu; Henegariu, Octavian; Moliterno, Jennifer; Louvi, Angeliki; Chan, Timothy A.; Tannheimer, Stacey L.; Pamir, M. Necmettin; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; Guenel, Murat
    Gliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.