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Kosuke Tanaka, Hirotaka Osada, Yuko Murakami-Tonami, Yoshitsugu Horio, Toyoaki Hida, Yoshitaka Sekido
Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation...
October 20, 2016: Cancer Letters
Verena Stahn, Inga Nagel, Susan Fischer-Huchzermeyer, Florian Oyen, Reinhard Schneppenheim, Stefan Gesk, Axel Bohring, Levan Chikobava, Peter Young, Burkhard Gess, Mathias Werner, Volker Senner, Anja Harder
Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells...
October 17, 2016: American Journal of Pathology
Mateusz Bujko, Marcin M Machnicki, Emilia Grecka, Natalia Rusetska, Ewa Matyja, Paulina Kober, Tomasz Mandat, Małgorzata Rydzanicz, Rafał Płoski, Romuald Krajewski, Wieslaw Bonicki, Tomasz Stokłosa, Janusz A Siedlecki
BACKGROUND: Rhabdoid meningioma is rare aggressive meningioma histological subtype, which develops predominantly through progression from less malignant tumors. Due to a low incidence the biological background is unknown. The aim of this study was to profile somatic mutations in four meningioma samples from the same patient, derived previously from four subsequent tumor resections. CASE DESCRIPTION: 58-year-old woman suffering from recurrent meningioma progressing from atypical to rhabdoid subtype...
October 15, 2016: World Neurosurgery
Daniel S Roberts, Steve Otto, Brian Chen, Kevin A Peng, Marc S Schwartz, Derald E Brackmann, John W House
OBJECTIVE: To evaluate whether an auditory brainstem implant (ABI) can impact levels of tinnitus in neurofibromatosis type-2 (NF2) patients who have undergone translabyrinthine craniotomy for vestibular schwannoma (VS) removal and to evaluate the burden of tinnitus in these patients. STUDY DESIGN: A retrospective case series and patient survey. SETTING: Tertiary neurotologic referral center. PATIENTS: NF2 patients who underwent translabyrinthine removal of VS and ABI placement between 1994 and 2015...
October 12, 2016: Otology & Neurotology
Melania Ester Mercado-Pimentel, Craig Miller, Daniela N Rolph, Edrick F Villalobos, Allison M Dunn, Prithvi M Mohan, Suzu Igarashi, Xiangdang Liu, Macken Yrun-Duffy, Neal K Patel, Cecilia M Read, Ross H Francis, Adelina Isabella Lane, Swaroop Murugesh, Abraham Jacob
HYPOTHESIS: p21-activated kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas. BACKGROUND: All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival. METHODS: The novel small molecule PAK inhibitors PI-8 and PI-15-tested in schwannoma and meningioma cells-perturb molecular signaling and induce cell death...
October 12, 2016: Otology & Neurotology
Wen-Bin Ou, Minmin Lu, Grant Eilers, Hailong Li, Jiongyan Ding, Xuli Meng, Yuehong Wu, Quan He, Qing Sheng, Hai-Meng Zhou, Jonathan A Fletcher
BACKGROUND: Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions. TP53 genomic mutations are uncommon in mesothelioma, and recent data indicate that p53 remains functional, and therefore is a potential therapeutic target in these cancers. In addition, the tumour suppressor NF2 is inactivated by genomic mechanisms in more than 80% of mesothelioma, causing upregulation of FAK activity. Because FAK is a negative regulator of p53, NF2 regulation of FAK-p53-MDM2 signalling loops were evaluated...
October 13, 2016: British Journal of Cancer
Sameer Agnihotri, Shahrzad Jalali, Mark R Wilson, Arnavaz Danesh, Mira Li, George Klironomos, Jonathan R Krieger, Alireza Mansouri, Osaama Khan, Yasin Mamatjan, Natalie Landon-Brace, Takyee Tung, Mark Dowar, Tiantian Li, Jeffrey P Bruce, Kelly E Burrell, Peter D Tonge, Amir Alamsahebpour, Boris Krischek, Pankaj Kumar Agarwalla, Wenya Linda Bi, Ian F Dunn, Rameen Beroukhim, Michael G Fehlings, Vera Bril, Stefano M Pagnotta, Antonio Iavarone, Trevor J Pugh, Kenneth D Aldape, Gelareh Zadeh
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q...
October 10, 2016: Nature Genetics
Marc S Schwartz, Eric P Wilkinson
OBJECTIVE: Auditory brainstem implants (ABIs), which have previously been used to restore auditory perception to deaf patients with neurofibromatosis type 2 (NF2), are now being utilized in other situations, including treatment of congenitally deaf children with cochlear malformations or cochlear nerve deficiencies. Concurrent with this expansion of indications, the number of centers placing and expressing interest in placing ABIs has proliferated. Because ABI placement involves posterior fossa craniotomy in order to access the site of implantation on the cochlear nucleus complex of the brainstem and is not without significant risk, we aim to highlight issues important in developing and maintaining successful ABI programs that would be in the best interests of patients...
September 26, 2016: Laryngoscope
Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A Rose Brannon, Lu Wang, Helen H Won, Patricia I Wang, Gouri J Nanjangud, Achim A Jungbluth, Wei Li, Virginia Ojeda, A Ari Hakimi, Martin H Voss, Nikolaus Schultz, Robert J Motzer, Paul Russo, Emily H Cheng, Filippo G Giancotti, William Lee, Michael F Berger, Satish K Tickoo, Victor E Reuter, James J Hsieh
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%)...
October 7, 2016: Nature Communications
Neville E Sanjana, Jason Wright, Kaijie Zheng, Ophir Shalem, Pierre Fontanillas, Julia Joung, Christine Cheng, Aviv Regev, Feng Zhang
The noncoding genome affects gene regulation and disease, yet we lack tools for rapid identification and manipulation of noncoding elements. We developed a CRISPR screen using ~18,000 single guide RNAs targeting >700 kilobases surrounding the genes NF1, NF2, and CUL3, which are involved in BRAF inhibitor resistance in melanoma. We find that noncoding locations that modulate drug resistance also harbor predictive hallmarks of noncoding function. With a subset of regions at the CUL3 locus, we demonstrate that engineered mutations alter transcription factor occupancy and long-range and local epigenetic environments, implicating these sites in gene regulation and chemotherapeutic resistance...
September 30, 2016: Science
Nicolas -Xavier Bonne, Rabih Aboukais, Marc Baroncini, Audrey Hochart, Pierre Leblond, Franck Broly, Frédérique Dubrulle, Jean-Paul Lejeune, Christophe Vincent
OBJECTIVE: This study aims to describe the clinical and molecular presentation of pediatric neurofibromatosis type 2 (NF2) and the subsequent management of vestibular schwannomas (VS) and hearing rehabilitation. METHODS: This is a single-center retrospective study of neurofibromatosis type 2 diagnosed before the age of 18 years old from 1997. Natural history of vestibular schwannomas and surgical outcomes were evaluated using volumetric MRI, hearing, and facial nerve assessment...
October 4, 2016: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
Neil S Patel, Kathryn M Van Abel, Michael J Link, Colin L W Driscoll, Jamie J Van Gompel, Brian A Neff, John I Lane, Matthew L Carlson
OBJECTIVE: Demonstrate the association of radiographic dural enhancement with increased tumor adherence at the porus acusticus, which may influence completeness of resection and facial nerve outcome. STUDY DESIGN: Case series with chart review. SETTING: Academic referral center. SUBJECTS AND METHODS: A total of 205 consecutive patients with histopathologically confirmed vestibular schwannoma (VS) were evaluated. Patients with tumors exhibiting dural enhancement on postgadolinium T1-weighted magnetic resonance imaging were identified and compared with matched controls...
October 4, 2016: Otolaryngology—Head and Neck Surgery
Satoru Kudose, Michael Kyriakos, Michael Magdi Awad
: Plexiform schwannoma (PS) is an uncommon variant of schwannoma characterized by a multinodular (plexiform) growth pattern. It comprises up to 5 % of all schwannomas. The association between PS and neurofibromatosis type 1 or type 2 (NF1/NF2) is only rarely reported. Most cases of PS occur in the skin and subcutaneous soft tissue, with only a few reports of digestive tract involvement. We describe an 18-year-old male with NF2 who had bilateral vestibular schwannomas and multiple cutaneous PSs, and a 3-year history of abdominal pain...
September 30, 2016: Clinical Journal of Gastroenterology
Hannah J D North, Deborah Mawman, Martin O'Driscoll, Simon R Freeman, Scott A Rutherford, Andrew T King, Charlotte Hammerbeck-Ward, D Gareth Evans, Simon K W Lloyd
In neurofibromatosis type 2 (NF2) bilateral vestibular schwannomas (VS) or their treatment usually results in bilateral hearing loss. Cochlear implantation (CI) was traditionally not used in these patients due to concern that retrocochlear disease would render the implant ineffective. This paper describes the auditory outcomes of CI in 13 patients with NF2 and includes patients with untreated VS and patients undergoing VS removal with cochlear nerve preservation. The non-user rate was 7.7%. Of the active users, median CUNY score was 98%, median BKB score in quiet was 90% and median BKB score in noise was 68%...
July 2016: Cochlear Implants International
Chang-Hyun Lee, Chun Kee Chung, Chi Heon Kim
PURPOSE: Although ependymomas occur in both the brain and the spine, the prognosis is quite varied by tumor location. Spinal ependymomas usually follow a relatively benign course with more favorable prognosis than that of the intracranial ependymomas. The aim of this study is to evaluate the genetic differences between spinal ependymomas and their intracranial counterparts using a meta-analysis. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library...
September 16, 2016: European Spine Journal
Srijit Das, Seong Lin Teoh
The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression...
September 7, 2016: Current Drug Targets
Sayaka Yuzawa, Hiroshi Nishihara, Shinya Tanaka
Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4...
October 2016: Brain Tumor Pathology
Jesse Lee Kresak, Meggen Walsh
The neurofibromatoses are a heterogeneous group of hereditary cancer syndromes that lead to tumors of the central and peripheral nervous systems, as well as other organ systems. By far the most common form is neurofibromatosis 1 (96%), followed by neurofibromatosis 2 (3%), and a more recently recognized, lesser known form, schwannomatosis. The diagnostic criteria, pathogenesis, molecular considerations, and clinical manifestations are discussed in this review article.
June 2016: Journal of Pediatric Genetics
Rohit Mehra, Pankaj Vats, Marcin Cieslik, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Aaron M Udager, Rui Wang, Jincheng Pan, Katayoon Kasaian, Robert Lonigro, Javed Siddiqui, Kumpati Premkumar, Ganesh Palapattu, Alon Weizer, Khaled S Hafez, J Stuart Wolf, Ankur Sangoi, Kiril Trpkov, Adeboye O Osunkoya, Ming Zhou, Giovanna A Giannico, Jesse K McKenney, Saravana M Dhanasekaran, Arul M Chinnaiyan
Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma with distinctive morphologic and cytogenetic features. Here we carry out whole exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n=22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSGs) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes while other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion...
September 7, 2016: Cancer Discovery
Hongbin Li, Barry M Gumbiner
The Hippo-YAP pathway mediates organ size control, contact inhibition, and tumorigenesis. It is a kinase cascade that inhibits the nuclear localization and transcriptional activities of YAP and TAZ. E-cadherin, cell junctions, polarity proteins, and the merlin/NF2 tumor suppressor activate the pathway to inhibit YAP/TAZ activity, while growth factor signaling inhibits the pathway to activate YAP/TAZ in the nucleus. We examined its role in the development of mouse mammary glands and tumor formation using gland reconstitution by transplantation of genetically modified mammary stem cells (MaSCs)...
September 6, 2016: Mammalian Genome: Official Journal of the International Mammalian Genome Society
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