Abstract |
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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Authors | K D Hadfield, M J Smith, J E Urquhart, A J Wallace, N L Bowers, A T King, S A Rutherford, D Trump, W G Newman, D G Evans |
Journal | Oncogene
(Oncogene)
Vol. 29
Issue 47
Pg. 6216-21
(Nov 25 2010)
ISSN: 1476-5594 [Electronic] England |
PMID | 20729918
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Topics |
- Adolescent
- Adult
- Child
- Chromosome Breakpoints
- Gene Dosage
(genetics)
- Genes, Neurofibromatosis 2
- Homozygote
- Humans
- Loss of Heterozygosity
(genetics)
- Mitosis
(genetics)
- Neurilemmoma
(genetics)
- Neurofibromatoses
(genetics)
- Neurofibromatosis 2
(genetics)
- Polymorphism, Single Nucleotide
(genetics)
- Recombination, Genetic
(genetics)
- Skin Neoplasms
(genetics)
- Young Adult
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