Analysis of Genetic Alterations in Patients Affected with Neurofibromatosis Type 2 and its Associated Tumors

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: 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.