title: Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas.
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.
authors: Department of Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors: K D
authors: KD
authors: Hadfield
authors: M J
authors: MJ
authors: Smith
authors: J E
authors: JE
authors: Urquhart
authors: A J
authors: AJ
authors: Wallace
authors: N L
authors: NL
authors: Bowers
authors: A T
authors: AT
authors: King
authors: S A
authors: SA
authors: Rutherford
authors: D
authors: D
authors: Trump
authors: W G
authors: WG
authors: Newman
authors: D G
authors: DG
authors: Evans
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D056905:Chromosome Breakpoints; D018628:Gene Dosage / Q000235:genetics; D016515:Genes, Neurofibromatosis 2; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008938:Mitosis / Q000235:genetics*; D009442:Neurilemmoma / Q000235:genetics; D017253:Neurofibromatoses / Q000235:genetics; D016518:Neurofibromatosis 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics; D055815:Young Adult