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Comprehensive DNA Copy Number Profiling of Meningioma Using a Chromosome 1 Tiling Path Microarray Identifies Novel Candidate Tumor Suppressor Loci

¹ Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden; ² Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden; and ³ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom

Requests for reprints: Jan P. Dumanski, Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Building C11, 3rd Floor, 751 85 Uppsala, Sweden. Phone: 46-18-6111096; Fax: 46-18-558931; E-mail: jan.dumanski{at}genpat.uu.se.

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.

Key Words: array-CGH • genomic microarray • deletion profiling • genomic clones • tiling path • DNA gains • copy number polymorphism

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