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Development and Application of Microarray-Based Comparative Genomic Hybridization: Analysis of Neurofibromatosis Type-2, Schwannomatosis and Related Tumors
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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. , p. 54
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 8
Keywords [en]
Genetics, Genomic microarray, Array-CGH, DNA copy number variation, Neurofibromatosis type-2, Schwannomatosis, Schwannoma, Meningioma, NF2, Chromosome 22
Keywords [sv]
Genetik
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-4786ISBN: 91-554-6149-2 (print)OAI: oai:DiVA.org:uu-4786DiVA, id: diva2:165763
Public defence
2005-03-17, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds vägen 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-02-23 Created: 2005-02-23 Last updated: 2018-01-13Bibliographically approved
List of papers
1. High-resolution profiling of an 11 Mb segment of human chromosome 22 in sporadic schwannoma using array-CGH.
Open this publication in new window or tab >>High-resolution profiling of an 11 Mb segment of human chromosome 22 in sporadic schwannoma using array-CGH.
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2003 In: International Journal of Oncology, ISSN 1019-6439, Vol. 22, no 3, p. 615-22Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92612 (URN)
Available from: 2005-02-23 Created: 2005-02-23Bibliographically approved
2. Development of NF2 gene specific, strictly sequence defined diagnostic microarray for deletion detection
Open this publication in new window or tab >>Development of NF2 gene specific, strictly sequence defined diagnostic microarray for deletion detection
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2003 In: Journal of molecular medicine, ISSN 0946-2716, Vol. 81, no 7, p. 443-51Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92613 (URN)
Available from: 2005-02-23 Created: 2005-02-23Bibliographically approved
3. A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications
Open this publication in new window or tab >>A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications
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2002 In: Human molecular genetics, ISSN 0964-6906, Vol. 11, no 25, p. 3221-9Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92614 (URN)
Available from: 2005-02-23 Created: 2005-02-23Bibliographically approved
4. Evidence for genetic aberrations of chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
Open this publication in new window or tab >>Evidence for genetic aberrations of chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92615 (URN)
Available from: 2005-02-23 Created: 2005-02-23 Last updated: 2010-01-13Bibliographically approved
5. Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci
Open this publication in new window or tab >>Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci
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2005 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 7, p. 2653-2661Article in journal (Refereed) Published
Abstract [en]

Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.

Keywords
Chromosome Aberrations, Chromosomes; Human; Pair 1/*genetics, DNA; Neoplasm/genetics, Gene Deletion, Gene Dosage, Genes; Tumor Suppressor, Humans, Loss of Heterozygosity, Meningeal Neoplasms/*genetics, Meningioma/*genetics, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Polymorphism; Genetic, Research Support; Non-U.S. Gov't
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92616 (URN)10.1158/0008-5472.CAN-04-3651 (DOI)15805262 (PubMedID)
Available from: 2005-02-23 Created: 2005-02-23 Last updated: 2017-12-14Bibliographically approved

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