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Evidence for genetic aberrations of chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-92615OAI: oai:DiVA.org:uu-92615DiVA: diva2:165761
Available from: 2005-02-23 Created: 2005-02-23 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Development and Application of Microarray-Based Comparative Genomic Hybridization: Analysis of Neurofibromatosis Type-2, Schwannomatosis and Related Tumors
Open this publication in new window or tab >>Development and Application of Microarray-Based Comparative Genomic Hybridization: Analysis of Neurofibromatosis Type-2, Schwannomatosis and Related Tumors
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neurofibromatosis type-2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral eighth cranial nerve schwannomas. However, the diagnostic criterion is complicated by the presence of a variable phenotype, with the severe form presenting with additional tumors such as peripheral schwannoma, meningioma and ependymoma. We constructed a microarray spanning 11Mb of 22q, encompassing the NF2 gene, to detect deletions in schwannoma. Forty seven patients were analyzed and heterozygous deletions were detected in 45% of tumors. Using this array-based approach, we also detected genetic heterogeneity in a number of samples studied. Despite the high sensitivity and the comprehensive series of studied schwannomas, no homozygous deletions affecting the NF2 gene were detected (paper I). In order to detect more subtle deletions within the NF2 locus, a higher-resolution gene-specific array was developed, for the detection of disease-causing deletions using a PCR-based non-redundant strategy. This novel approach for array construction significantly increased the reliability and resolution of deletion-detection within the NF2 locus (paper II). To further expand the coverage of the 11 Mb microarray, we constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number. This 22q array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb (paper III). Using this array, we analyzed sporadic and familial schwannomatosis samples, which revealed two commonly deleted regions within the immunoglobulin lambda locus and the GSTT1/CABIN1 locus. These regions were further characterized using higher-resolution non-redundant arrays, bioinformatic tools, positional cloning and mutational screening. Missense mutations were detected in the CABIN1 gene, which may contribute to the pathogenesis of schwannomatosis and therefore requires further study (paper IV). Meningioma is the second most common NF2-associated tumor and loss of 1p has been previously established as a major genetic factor for disease initiation/progression and also correlates with increased morbidity. We analyzed 82 meningiomas using a chromosome 1 tiling-path genomic microarray. The distribution of aberrations detected supports the existence of at least four regions on chromosome 1, which are important for meningioma tumorigenesis (paper V).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 54 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 8
Genetics, Genomic microarray, Array-CGH, DNA copy number variation, Neurofibromatosis type-2, Schwannomatosis, Schwannoma, Meningioma, NF2, Chromosome 22, Genetik
National Category
Medical Genetics
urn:nbn:se:uu:diva-4786 (URN)91-554-6149-2 (ISBN)
Public defence
2005-03-17, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds vägen 20, Uppsala, 09:15
Available from: 2005-02-23 Created: 2005-02-23Bibliographically approved

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