Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas

Biallelic inactivation of the NF2 gene occurs in the majority of schwannomas. This usually involves a combination of a point mutation or multiexon deletion, in conjunction with either a second point mutation or loss of heterozygosity (LOH). We have performed DNA sequence and dosage analysis of the N...

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Bibliographic Details
Published in:	Oncogene Vol. 29; no. 47; pp. 6216 - 6221
Main Authors:	Hadfield, K D, Smith, M J, Urquhart, J E, Wallace, A J, Bowers, N L, King, A T, Rutherford, S A, Trump, D, Newman, W G, Evans, D G
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25.11.2010 Nature Publishing Group
Subjects:	631/208/68 692/699/67/1922 Acoustic neuroma Adolescent Adult Apoptosis Biological and medical sciences Cancer Cell Biology Cell division Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Child Chromosome 22 Chromosome Breakpoints Copy number Fundamental and applied biological sciences. Psychology Gene deletion Gene Dosage - genetics Gene mutations Genes, Neurofibromatosis 2 Genetic aspects Genetic disorders Genotype & phenotype Genotyping Health aspects Heterozygosity Homozygote Human Genetics Humans Hybridization Internal Medicine Loss of heterozygosity Loss of Heterozygosity - genetics Medical sciences Medicine Medicine & Public Health Mitosis - genetics Molecular and cellular biology Mutation Nervous system Neurilemmoma - genetics Neurofibromatoses - genetics Neurofibromatosis Neurofibromatosis 2 Neurofibromatosis 2 - genetics Neurofibromin 2 Neurological disorders Neurology Nucleotide sequence Oncology original-article Point mutation Polymorphism, Single Nucleotide - genetics Recombination Recombination, Genetic - genetics Risk factors Schwann cells Sequence analysis Single nucleotide polymorphisms Skin Neoplasms - genetics Tumors Tumors of the nervous system. Phacomatoses Vestibular system Young Adult United Kingdom mitotic recombination schwannomatosis vestibular schwannoma Nervous system diseases SMARCB1 Mitotic recombination Sporadic Neurinoma Loss of heterozygosity Benign neoplasm NF2 Carcinogenesis
ISSN:	0950-9232, 1476-5594, 1476-5594
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Summary:	Biallelic inactivation of the NF2 gene occurs in the majority of schwannomas. This usually involves a combination of a point mutation or multiexon deletion, in conjunction with either a second point mutation or loss of heterozygosity (LOH). We have performed DNA sequence and dosage analysis of the NF2 gene in a panel of 239 schwannoma tumours: 97 neurofibromatosis type 2 (NF2)-related schwannomas, 104 sporadic vestibular schwannomas (VS) and 38 schwannomatosis-related schwannomas. In total, we identified germline NF2 mutations in 86 out of 97 (89%) NF2 patients and a second mutational event in 77 out of 97 (79%). LOH was by far the most common form of second hit. A combination of microsatellite analysis with either conventional comparative genomic hybridization (CGH) or multiplex ligation-dependent probe amplification (MLPA) identified mitotic recombination (MR) as the cause of LOH in 14 out of 72 (19%) total evaluable tumours. Among sporadic VS, at least one NF2 mutation was identified by sequence analysis or MLPA in 65 out of 98 (66%) tumours. LOH occurred in 54 out of 96 (56%) evaluable tumours, but MR only accounted for 5 out of 77 (6%) tested. LOH was present in 28 out of 34 (82%) schwannomatosis-related schwannomas. In all eight patients who had previously tested positive for a germline SMARCB1 mutation, this involved loss of the whole, or part of the long arm, of chromosome 22. In contrast, 5 out of 22 (23%) tumours from patients with no germline SMARCB1 mutation exhibited MR. High-resolution Affymetrix SNP6 genotyping and copy number (CN) analysis (Affymetrix, Santa Clara, CA, USA) were used to determine the chromosomal breakpoint locations in tumours with MR. A range of unique recombination sites, spanning approximately 11.4 Mb, were identified. This study shows that MR is a mechanism of LOH in NF2 and SMARCB1 -negative schwannomatosis-related schwannomas, occurring less frequently in sporadic VS. We found no evidence of MR in SMARCB1 -positive schwannomatosis, suggesting that susceptibility to MR varies according to the disease context.
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ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/onc.2010.363