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Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, 16- p.Article in journal (Refereed) Published
Abstract [en]

Background: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. Results: 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. Conclusion: 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.

Place, publisher, year, edition, pages
2007. Vol. 8, 16- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94068DOI: 10.1186/1471-2164-8-16ISI: 000244054200001PubMedID: 17222329OAI: oai:DiVA.org:uu-94068DiVA: diva2:167789
Available from: 2006-03-10 Created: 2006-03-10 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Analysis of Genetic Alterations in Patients Affected with Neurofibromatosis Type 2 and its Associated Tumors
Open this publication in new window or tab >>Analysis of Genetic Alterations in Patients Affected with Neurofibromatosis Type 2 and its Associated Tumors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral vestibular schwannomas (VS). Patients affected by a severe NF2 phenotype also presents with peripheral schwannomas, meningiomas and ependymomas. The closely related disorder schwannomatosis also displays multiple schwannomas, but never VS. Mutation screening of the NF2 gene in the above mentioned tumors did not identify mutations in numerous of cases. We analyzed the DNA sequence covering the NF2 locus in order to identify evolutionarily conserved non-genic sequences (CNGs) with unknown regulatory function (paper I). The aim was to analyze CNGs for mutations in DNA derived from patients affected by NF2 associated tumors. During mutation analysis of the coding part of NF2 and within the CNGs defined in paper I, were mutations detected in 39% of sporadic meningiomas (paper II). Two candidate regions were identified on 22q using array-CGH. Methylation profiling did not identify methylation of the NF2 promoter in these tumors. Sporadic schwannomas were profiled for CNV using a 22q genomic array in the search for putative gene(s) that in addition to NF2 could be involved in the development of schwannoma and/or schwannomatosis (paper III). The predominant aberration identified was monosomy 22. Terminal and interstitial deletions encompassing the NF2 gene were detected in tumor DNA and eight loci affected by CNV in constitutional DNA. Some of these CNVs are unlikely to be phenotypically neutral, considering their size and gene content. Two schwannomatosis candidate regions were identified on 22q using array-CGH (paper IV). These regions were further characterized by a PCR-product based array with higher resolution. Rearrangements of the immunoglobulin lambda (IGL) locus detected were restricted to schwannomatosis patients. In the second candidate region spanning GSTT1 and CABIN1 genes, was frequent copy number polymorphism at the GSTT1 locus identified. We further describe missense mutations in the CABIN1 gene, making this gene a plausible candidate which may contribute to the pathogenesis of these disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 113
Keyword
Molecular biology, Neurofibromatosis type 2, schwannoma, schwannomatosis, meningioma, array-CGH, chromosome 22, DNA copy number variation, methylation, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-6511 (URN)91-554-6477-7 (ISBN)
Public defence
2006-03-31, Rudbecksalen, Rudbeck laboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
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Available from: 2006-03-10 Created: 2006-03-10 Last updated: 2011-02-15Bibliographically approved

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