Browsing by Author "Erson-Omay, E. Zeynep"

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Associations of meningioma molecular subgroup and tumor recurrence
(OXFORD UNIV PRESS INC, 2021-01-01) Youngblood, Mark W.; Miyagishima, Danielle F.; Jin, Lan; Gupte, Trisha; Li, Chang; Duran, Daniel; Montejo, Julio D.; Zhao, Amy; Sheth, Amar; Tyrtova, Evgeniya; Ozduman, Koray; Iacoangeli, Francesco; Peyre, Matthieu; Boetto, Julien; Pease, Matthew; Avsar, Timucin; Huttner, Anita; Bilguvar, Kaya; Kilic, Turker; Pamir, M. Necmettin; Amankulor, Nduka; Kalamarides, Michel; Erson-Omay, E. Zeynep; Gunel, Murat; Moliterno, Jennifer
Background. We and others have identified mutually exclusive molecular subgroups of meningiomas
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.
IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
(NATURE PUBLISHING GROUP, 2016-01-01) Oktay, Yavuz; Ulgen, Ege; Can, Ozge; Akyerli, Cemaliye B.; Yuksel, Sirin; Erdemgil, Yigit; Durasi, I. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Sevin; Ozpinar, Aysel; Huse, Jason T.; Sav, M. Aydin; Flanagan, Adrienne; Gunel, Murat; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, Koray
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52
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.
Longitudinal analysis of treatment-induced genomic alterations in gliomas
(BIOMED CENTRAL LTD, 2017-01-01) Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bulent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; Ozduman, Koray; Carrion-Grant, Geneive; Clark, Victoria E.; Caglar, Caner; Bakircioglu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Gunel, Murat
Background: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy
Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
(OXFORD UNIV PRESS INC, 2015-01-01) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; Ozduman, Koray; Koksal, Yavuz; Li, Jie; Harmanci, Akdes Serin; Clark, Victoria; Carrion-Grant, Geneive; Baranoski, Jacob; Caglar, Caner; Barak, Tanyeri; Coskun, Suleyman; Baran, Burcin; Kose, Dogan; Sun, Jia; Bakircioglu, Mehmet; Gunel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Gunel, Murat
Background. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these ``ultramutated{''} tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.