Genomic Analysis of Non-
 NF2
 Meningiomas Reveals Mutations in
 TRAF7
 ,
 KLF4
 ,
 AKT1
 , and
 SMO

Clark, Victoria; Erson‐Omay, E. Zeynep; Serin, Akdes; Yin, Jun; Cotney, Justin; Özduman, Koray; Avşar, Timuçin; Li, Jie; Murray, Phillip B.; Henegariu, Octavian; Yılmaz, Selim; Günel, Jennifer Moliterno; Carrión-Grant, Geneive; Yılmaz, Baran; Grady, Conor; Tanrıkulu, Bahattin; Bakırcıoğlu, Mehmet; Kaymakçalan, Hande; Çağlayan, Ahmet Okay; Sencar, Leman; Ceyhun, Emre; Atik, Ahmet; Bayri, Yaşar; Bai, Hanwen; Kolb, Luis; Hebert, Ryan; Omay, Sacit Bulent; Mishra-Gorur, Ketu; Choi, Murim; Overton, John D.; Holland, Eric C.; Mane, Shrikant; State, Matthew W.; Bilgüvar, Kaya; Baehring, Joachim M.; Gutin, Philip H.; Piepmeier, Joseph M.; Vortmeyer, Alexander O.; Brennan, Cameron; Pamir, M. Necmettin; Kılıç, Türker; Lifton, Richard P.; Noonan, James P.; Yasuno, Katsuhito; Günel, Murat

doi:10.1126/science.1233009

Cited by 734 publications

(742 citation statements)

References 32 publications

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“…Zhu et al (2009) showed that in primary cortical neuron cultures, KLF4 overexpression induced the activation of caspase-3 in response to glutamate excitotoxicity. In a recent Science paper, Moore et al detected no differences in survival between KLF4-and controltransfected hippocampal neurons, although KLF4 suppresses axon and dendrite initiation and elongation in this system (Clark et al 2013). Our data presented herein support the conclusion that KLF4 is an antiapoptotic factor.…”

Section: Discussionsupporting

confidence: 81%

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Sun

Cunningham

et al. 2014

AGE

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Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H 2 O 2 )-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H 2 O 2 -caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC.Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF-or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H 2 O 2 -stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death.

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Section: Discussionsupporting

confidence: 81%

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Sun

Cunningham

et al. 2014

AGE

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“…77 In this regard, clinical correlation with the rapidly accumulating genetic data on meningiomas will certainly also help to tailor treatment recommendations for Grade II and III meningiomas. 7,14,15 conclusions This study reviews reported management strategies and outcomes for patients with WHO Grade II and III meningiomas in an effort to develop a logical algorithm for evidence-based treatment recommendations. The evidence primarily supports safe GTR of AMs or, if GTR is not feasible, STR with adjuvant radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas

Sun¹,

Hawasli²,

Huang

et al. 2015

FOC

115

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The management of WHO Grade II “atypical” meningiomas (AMs) and Grade III “malignant” meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM.

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“…Of note, either AKT1 or β-catenin mutation in malignant tumors usually co-occurs with other driver genomic alterations (22,30,31). However, AKT1 mutations in benign tumors, such as meningiomas and PSHs, and β-catenin mutations in pilomatricoma do not usually co-occur with each other or other known driver mutations (32)(33)(34). It is possible that AKT1 or β-catenin mutation alone is able to produce a benign tumor but not a malignant tumor.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

Jung

Kim

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pulmonary sclerosing hemangioma (PSH) is a benign tumor with two cell populations (epithelial and stromal cells), for which genomic profiles remain unknown. We conducted exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3 of 68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Because the AKT1 mutations were not found to cooccur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be the singlemost common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas, including a high rate of AKT1 mutation in PSHs. These genomic features of PSH identified in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors.pulmonary sclerosing hemangioma | whole-exome sequencing | AKT1 mutation | copy number alteration

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Genomic Analysis of Non- NF2 Meningiomas Reveals Mutations in TRAF7 , KLF4 , AKT1 , and SMO

Cited by 734 publications

References 32 publications

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

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