Neurofibromatosis 2 and malignant mesothelioma

Baser, Michael E.; Rienzo, Assunta De; Altomare, Deborah A.; Balsara, Binaifer; Hedrick, Nicolé M.; Gutmann, David H.; Pitts, Lawrence H.; Jackler, Robert K.; Testa, Joseph R.

doi:10.1212/wnl.59.2.290

Cited by 37 publications

(24 citation statements)

References 8 publications

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“…However, NF2 patients exposed to asbestos might be at a higher risk to develop mesothelioma, as recently suggested by Baser et al (2002) in a case report study. Moreover, Pylkkanen et al (2002) reported allele losses preferentially involving the NF2 gene, in human MM.…”

Section: Introductionmentioning

confidence: 63%

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Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

et al. 2003

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Biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2 KO3/ þ ), after intraperitoneal inoculation of crocidolite fibres. Asbestos-exposed Nf2 KO3/ þ mice developed tumoural ascites and mesothelioma at a higher frequency than their wild-type (WT) counterparts (Po0.05). Six out of seven mesothelioma cell lines established from neoplastic ascitic fluids of Nf2 KO3/ þ mice exhibited loss of the WT Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results show the importance of the NF2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumour suppressor gene inactivation, and suggest that NF2 gene mutation may be a susceptibility factor to asbestos.

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Section: Introductionmentioning

confidence: 63%

“…Mesothelioma is not a characteristic feature of NF2 patients, but one case of peritoneal mesothelioma in an NF2 patient exposed to asbestos has been recently reported (Baser et al, 2002). The relation between asbestos exposure and incidence of MM suggests the role of asbestos exposure in biallelic NF2 inactivation.…”

Section: Discussionmentioning

confidence: 99%

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

et al. 2003

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“…Studies have also suggested a potential role for NF2 in mesothelioma (Bianchi et al, 1995;Baser et al, 2002) and SV40 DNA and T-antigen protein have been detected in complex with p53 in human mesothelioma (Carbone et al, 1997;Testa et al, 1998). As mentioned above, p53 is often overexpressed in mpnst, although it should be noted that overexpression of p53 in this model is not indicative of its mutation, as T-antigen binds to wild-type p53.…”

Section: Discussionmentioning

confidence: 99%

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

et al. 2004

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“…may have increased susceptibility to malignant mesothelioma (17). However, the clinicopathologic consequences of NF2 alterations of malignant mesothelioma are not well defined.…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

Altomare¹,

Vaslet

Skele³

et al. 2005

Cancer Research

146

143

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Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf 2 (+/À) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf 2 (+/À) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf 2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf 2 (+/À) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf 2 (+/À) mice showed frequent homologous deletions of the Cdkn2a/ Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/À) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities. (Cancer Res 2005; 65(18): 8090-5)

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Neurofibromatosis 2 and malignant mesothelioma

Cited by 37 publications

References 8 publications

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

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