CHARACTERIZATION OF THE RAT NEUROFIBROMATOSIS-2 GENE AND ITS INVOLVEMENT IN ASBESTOS-INDUCED MESOTHELIOMA

The neurofibromatosis 2 (NF2) tumor suppressor gene was recently impli cated in the genesis of human mesothelioma. To investigate the role of this tumor suppressor gene in rat asbestos-induced mesothelioma, a co mmonly used model for the human disease, we characterized the rat homo logue of NF2 and examined rat chrysotile-induced primary mesotheliomas and cell lines derived from chrysotile- and crocidolite-induced mesot heliomas for alterations in this gene. The coding sequence obtained fo r the rat NF2 gene had 90% nucleotide homology with the human NF2 gene . The rat NF2 gene was ubiquitously expressed as a 4.4-kb transcript i n normal rat tissues as well as in rat mesothelioma cell lines. Revers e transcription-polymerase chain reaction analysis to examine splicing of NF2 exons in mesothelioma cells indicated that the exon splicing p attern was similar in normal and neoplastic cells. To determine if mut ations had occurred in the NF2 coding region in rat mesotheliomas, sin gle-strand conformation polymorphism analysis and direct sequencing we re used to screen 10 primary tumors and six tumor cell lines. No DNA s equence alterations were observed in any of the rat mesothelioma sampl es examined. These findings contrast with data reported previously for human mesotheliomas, in which the NF2 gene was found to be mutated in 40% of cases. Taken together, these data suggest that the role of NF2 in the development of rodent asbestos-induced mesothelioma may differ significantly from the role in the human disease. (C) 1997 Wiley-Liss , Inc.