A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.
ABSTRACT Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral vestibular schwannomas and other central nervous system tumors including multiple meningiomas. Genetic linkage studies and investigations of both sporadic and familial tumors suggest that NF2 is caused by inactivation of a tumor suppressor gene in chromosome 22q12. We have identified a candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients. The candidate gene encodes a 587 amino acid protein with striking similarity to several members of a family of proteins proposed to link cytoskeletal components with proteins in the cell membrane. The NF2 gene may therefore constitute a novel class of tumor suppressor gene.
SourceAvailable from: Malak Abedalthagafi[Show abstract] [Hide abstract]
ABSTRACT: Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile - polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.Oncotarget 09/2014; · 6.63 Impact Factor
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ABSTRACT: Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-high-throughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy.American Journal of Translational Research 01/2014; 6(5):471-93. · 3.23 Impact Factor
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ABSTRACT: Introduction: The molecular pathogenesis of the inherited tumour predisposition syndrome, neurofibromatosis type 2 (NF2), has been the subject of intense scrutiny in recent years. Better understanding of the multiple physiological roles of the NF2 protein Merlin, and increasing availability of molecularly targeted therapies have for the first time made medical treatments a feasible option for patients with NF2.Areas covered: In this report we describe the clinical features of NF2, we summarise recent advances in NF2 biology and describe the evidence underlying current management, focusing particularly on the activity of anti-angiogenic agents and on therapies that target Merlin’s interaction partners.Expert opinion: The anti-angiogenic agent bevacizumab is the first medical therapy to show real promise in the treatment of this disease, but its effects are limited to disease stabilisation and to partial imaging and hearing responses. The results of early-phase trials targeted towards Merlin’s partners have been disappointing to date, but given the breadth of Merlin’s interactions, it may be unrealistic to expect single pathway inhibition to have a measurable effect. Future work should focus on rational combinations of targeted agents and on studies to ameliorate the phenotypic features of NF2, rather than focusing solely on the management of established tumours.02/2015; DOI:10.1517/21678707.2015.1014800