Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation

Warren, C; James, Louise A; Ramsden, R. T.; Wallace, Andrew; Baser, Michael E.; Varley, Jennifer; Evans, D. Gareth

doi:10.1136/jmg.40.11.802

Cited by 76 publications

(51 citation statements)

References 46 publications

(35 reference statements)

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“…The SRI is located at 9q34 and this region was found amplified in two insulinomas. Gain and/or amplification of this region have been reported in other neoplasms, including neuroendocrine tumors (Dannenberg et al 2000, Figueiredo et al 2000, Garcia et al 2002, schwannomas (Warren et al 2003), and enteropathy-type T-cell lymphomas (Baumga¨rtner et al 2003). There are several candidate genes localized in this region, i.e.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal instability predicts metastatic disease in patients with insulinomas

Jonkers

Claessen²,

Perren³

et al. 2005

Endocrine Related Cancer

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Endocrine pancreatic tumors (EPTs) comprise a highly heterogeneous group of tumors with different clinical behavior and genetic makeup. Insulinomas represent the predominant syndromic subtype of EPTs. The metastatic potential of insulinomas can frequently not be predicted using histopathological criteria, and also molecular markers indicating malignant progression are unreliable because of the small number of cases per subtype studied so far. For the identification of reliable indicators of metastatic disease, we investigated 62 sporadic insulinomas (44 benign and 18 tumors with metastases) by means of comparative genomic hybridization (CGH). In addition, the role of MEN1 (multiple endocrine neoplasia type 1) gene mutations was determined to assess specific chromosomal alterations associated with dysfunction of this endocrine tumor-related tumor suppressor gene. Only one case with a somatic MEN1 mutation was identified (1527del7bp), indicating that the MEN1 gene plays a minor pathogenic role in sporadic insulinomas. CGH analysis revealed that the total number of aberrations per tumor differs strongly between the benign and the malignant group (4.2 vs 14.1; P<0.0001). Furthermore, chromosome 9q gain was found to be the most frequent aberration in both benign and malignant insulinomas, whereas chromosome 6q losses and 12q, 14q and 17pq gains are strongly associated with metastatic disease. Our study shows that chromosomal instability, as defined by ‡5 gains together with ‡5 losses, or total number of gains and losses ‡8, rather than parameters such as tumor size and proliferation index, is the most powerful indicator for the development of metastatic disease in patients with sporadic insulinoma.

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Section: Discussionmentioning

confidence: 99%

Chromosomal instability predicts metastatic disease in patients with insulinomas

Jonkers

Claessen²,

Perren³

et al. 2005

Endocrine Related Cancer

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“…Of note, the effect of NF2 loss on chromosome instability and malignant transformation seems to be tissue specific because different situations occur in various tumor types having NF2 gene mutations as common denominator. In schwannoma, a benign tumor of the peripheral nervous system, NF2 inactivation is universal, necessary, and sufficient for tumor development in the absence of chromosome instability (38,39). Rare cases of schwannomas undergo malignant transformation, generally after radiation therapy, which possibly induces p53 mutations (40).…”

Section: Nf2 Loss Is Associated With Chromosome Instability In Progrementioning

confidence: 99%

Genomic Profiling Reveals Alternative Genetic Pathways of Meningioma Malignant Progression Dependent on the UnderlyingNF2Status

Goutagny

Yang

Zucman‐Rossi

et al. 2010

Clinical Cancer Research

105

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Purpose: Meningiomas are the most common central nervous system tumors in the population of age 35 and older. WHO defines three grades predictive of the risk of recurrence. Clinical data supporting histologic malignant progression of meningiomas are sparse and underlying molecular mechanisms are not clearly depicted.Experimental Design: We identified genetic alterations associated with histologic progression of 36 paired meningioma samples in 18 patients using 500K SNP genotyping arrays and NF2 gene sequencing.Results: The most frequent chromosome alterations observed in progressing meningioma samples are early alterations (i.e., present both in lower-and higher-grade samples of a single patient). In our series, NF2 gene inactivation was an early and frequent event in progressing meningioma samples (73%). Chromosome alterations acquired during progression from grade I to grade II meningioma were not recurrent. Progression to grade III was characterized by recurrent genomic alterations, the most frequent being CDKN2A/CDKN2B locus loss on 9p.Conclusion: Meningiomas displayed different patterns of genetic alterations during progression according to their NF2 status: NF2-mutated meningiomas showed higher chromosome instability during progression than NF2-nonmutated meningiomas, which had very few imbalanced chromosome segments. This pattern of alterations could thus be used as markers in clinical practice to identify tumors prone to progress among grade I meningiomas. Clin Cancer Res; 16(16); 4155-64. ©2010 AACR.

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“…The method for CGH was previously described in (James and Varley, 1996;James et al, 1999;Warren et al, 2003).…”

Section: Patient Tumoursmentioning

confidence: 99%

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

et al. 2010

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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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Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation

Cited by 76 publications

References 46 publications

Chromosomal instability predicts metastatic disease in patients with insulinomas

Chromosomal instability predicts metastatic disease in patients with insulinomas

Genomic Profiling Reveals Alternative Genetic Pathways of Meningioma Malignant Progression Dependent on the UnderlyingNF2Status

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

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