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Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus
Caisa M Hansson, Patrick G Buckley, Giedre Grigelioniene, Arkadiusz Piotrowski, Anders R Hellstr?m, Kiran Mantripragada, Caroline Jarbo, Tiit Mathiesen, Jan P Dumanski
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-16
Abstract: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (~550 kb and ~250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample.We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.Meningiomas are the most frequently occurring intracranial tumors. Clinically treated meningiomas comprise approximately 13–26% of all primary brain tumors [1]. Epidemiological studies indicate that ~90% of all meningiomas are asymptomatic [2]. The majority are benign, slowly growing, solitary and sporadic tumors, but atypical or malignant meningioma constitutes approximately 10% of all cases. Meningiomas are thought to be derived from the arachnoid cap cells of the lepto
Bevacizumab Treatment for Meningiomas in NF2: A Retrospective Analysis of 15 Patients  [PDF]
Fabio P. Nunes, Vanessa L. Merker, Dominique Jennings, Paul A. Caruso, Emmanuelle di Tomaso, Alona Muzikansky, Fred G. Barker, Anat Stemmer-Rachamimov, Scott R. Plotkin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059941
Abstract: Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas.
THE ATTRIBUTE INHERITANCE IN NF2 RELATIONAL MODEL
NF2关系模型与属性继承

Li Tianzhu,
李天柱

软件学报 , 1995,
Abstract: Combining object oriented model with value-based model would help getting the merits of both models. In this paper, based on NF2 relational model with composited tuple identity, the operations of projection if and natural join keeping the nested structure of relations, are given. From this, the authors have studied the semantics and formallied definition for class, subclass, attribute inheritance in NF2 relational model, introducing a special attribute R" and concept of S-subclass, discussed the common sub class and multiple inheritance. All of the discussions are based on composited tuple identity, possessing the features in O-O model.
Genetic and Epigenetic Alterations of the NF2 Gene in Sporadic Vestibular Schwannomas  [PDF]
Jong Dae Lee, Tae Jun Kwon, Un-Kyung Kim, Won-Sang Lee
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030418
Abstract: Background Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. Methodology/Principal Findings NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. Conclusions/Significance The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.
Neurofibromatosis type 2 (NF2): A clinical and molecular review
D Gareth R Evans
Orphanet Journal of Rare Diseases , 2009, DOI: 10.1186/1750-1172-4-16
Abstract: Neurofibromatosis type 2(NF2), Bilateral acoustic neurofibromatosis, Central neurofibromatosis. OMIM #101000Neurofibromatosis type 2 (NF2) is a dominantly inherited tumour prone disorder characterised by the development of multiple schwannomas and meninigiomas [1]. The disease can be diagnosed when a pathogenic mutation in the NF2 gene is identified or when the criteria in table 1[1] are fulfilled.When using established clinical diagnostic criteria [1] and based on mutations in the NF2 gene [2,3] assessment of the frequency of NF2 in the population can be made. This is complicated by the high rate of mosaicism [4]. There have only been two epidemiological studies of NF2 one in North West England [5,6], [Evans DG et al. Birth incidence and prevalence of tumour prone syndromes: estimates from a UK genetic family register service. Am J Med Genet 2009. unpublished] and one in Finland [7]. The incidence of NF2 was initially reported as 1:33–40,000 individuals in a 4 million population in England [5]. Disease prevalence was somewhat lower at 1: 200,000. However, a recent update suggests that the incidence may be as high as 1:25,000 [6]. Disease prevalence has now risen to around 1 in 60,000 due to earlier diagnosis and better survival due to improved treatment [Evans DG et al. Birth incidence and prevalence of tumour prone syndromes: estimates from a UK genetic family register service. Am J Med Genet 2009. unpublished]. A lower incidence of 1 in 87,410 was reported in a 1.7 million population in Finland [7].NF2, in contrast to neurofibromatosis type 1 (NF1) is characterised by the development of schwannomas, meningiomas and ependymomas, with the great majority of patients developing bilateral schwannoma involvement of the superior vestibular branch of the eighth cranial nerve [1]. Although the disease is still classified as "neurofibromatosis", neurofibromas are relatively infrequent. The first clear description of NF2 was in 1822 by Wishart [8]. NF1 was fully delineated
Association of lower cranial nerve schwannoma with spinal ependymoma in ? NF2.
Kumar R,Sharma K,Chhabra D
Neurology India , 1999,
Abstract: A 15 year old male, who had earlier been operated for intraspinal intramedullary ependymoma, subsequently developed a right cerebello pontine (CP) angle mass. A diagnosis of right CP angle ependymoma was considered, in view of established histology of previously operated spinal lesion. Histopathological examination of the well defined extra-axial mass, which was attached with ninth cranial nerve, however revealed a schwannoma. A diagnosis of Neurofibromatosis-2 (NF2) is strongly suspected, because of well established fact, that the spinal ependymomas may have association with lower cranial nerve schwannomas in NF2. Cranial and spinal MRI screening for early diagnosis of associated, asymptomatic lesions, in suspected cases of NF2, particularly in children, is recommended.
Mapping of MN1 Sequences Necessary for Myeloid Transformation  [PDF]
Ayten Kandilci, Jacqueline Surtel, Laura Janke, Geoffrey Neale, Sabrina Terranova, Gerard C. Grosveld
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061706
Abstract: The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1’s in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12–228 (Δ12–228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Δ12–228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Δ12–228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.
The Leukemia-Associated Fusion Protein MN1-TEL Blocks TEL-Specific Recognition Sequences  [PDF]
W. Martijn ter Haar, Magda A. Meester-Smoor, Karel H. M. van Wely, Claudia C. M. M. Schot, Marjolein J. F. W. Janssen, Bart Geverts, Jacqueline Bonten, Gerard C. Grosveld, Adriaan B. Houtsmuller, Ellen C. Zwarthoff
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046085
Abstract: The leukemia-associated fusion protein MN1-TEL combines the transcription-activating domains of MN1 with the DNA-binding domain of the transcriptional repressor TEL. Quantitative photobleaching experiments revealed that ~20% of GFP-tagged MN1 and TEL is transiently immobilised, likely due to indirect or direct DNA binding, since transcription inhibition abolished immobilisation. Interestingly, ~50% of the MN1-TEL fusion protein was immobile with much longer binding times than unfused MN1 and TEL. MN1-TEL immobilisation was not observed when the TEL DNA-binding domain was disrupted, suggesting that MN1-TEL stably occupies TEL recognition sequences, preventing binding of factors required for proper transcription regulation, which may contribute to leukemogenesis.
nf2关系模型与属性继承  [PDF]
李天柱?
软件学报 , 1995,
Abstract: 将面向对象模型与面向值的模型相结合,可兼得二者的优点.本文基于具有组合元组标识的nf2关系模型给出了强调嵌套结构特征的关系运算投影iis和自然连接,并在此基础上研究nf2关系数据模型中的类、子类及其间的属性继承的语义及形式化定义;引入了s-子类的概念;研究了公共子类及多属性继承的特征.所有的讨论基于组合元组标识,具有较强的面向对象模型的特征.
Chromosome 15q24 microdeletion syndrome
Pilar L Magoulas, Ayman W El-Hattab
Orphanet Journal of Rare Diseases , 2012, DOI: 10.1186/1750-1172-7-2
Abstract: Chromosome 15q24 deletion syndrome15q24 deletion syndrome15q24 microdeletion syndromeChromosome 15q24 microdeletion syndrome is a rare and novel microdeletion syndrome characterized by pre- and post-natal growth retardation, intellectual disability, distinct facial features, and genital, skeletal, and digital anomalies. Additional common features include hypotonia, behavioral problems, and recurrent infections (table 1) [1-10]. Although some of the characteristic features may be non-specific, the combination of these findings should prompt the clinician to suspect this diagnosis. Most of the deletions are between 1.7 to 6.1 megabases (Mb) in size, with the smallest region of overlap (SRO) spanning a 1.2 Mb region (Figure 1) [1-10]. Routine high-resolution karyotypes typically do not detect the deletion and all individuals with 15q24 deletion syndrome were diagnosed by using array comparative genomic hybridization (CGH) [1-10].The incidence of 15q24 deletion syndrome is unknown. To date, there have been 19 published reports of individuals with 15q24 deletion syndrome in which clinical information and detailed mapping of the genomic breakpoints are available [1-10]. The first case was reported in 2007 by Sharp et al [1]. Prior to this time, the widespread use of array CGH was limited, therefore the diagnosis may have gone undetected and undiagnosed. With the advent of array CGH, we anticipate that the present number of reported cases represents an underestimate of the actual prevalence of the disorder. A recent study by Cooper et al [11] reviewed 15,767 cases with intellectual disability and various congenital defects referred to their laboratory for array CGH. They identified 15q24 deletion in nine patients with intellectual disability, for an incidence of approximately 1 in 1751 in this population. This would make it approximately 1/10th as frequent as 22q11.2 deletion syndrome which was identified in 96 cases with intellectual disability (~1 in 164). Given these es
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