title: Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma.
abstract: Human malignant mesothelioma (HMM) is an aggressive malignancy mainly caused by exposure to asbestos fibers. Here we investigated tumor suppressor genes in mesothelioma cells from tumoral ascites developed in mice exposed to asbestos (asb) fibers and in 12 HMM cell cultures. Mutations in Nf2, p16/Cdkn2a, p19/Arf and Trp53 genes and protein expression of p15/Cdkn2b and Cdk4 were analyzed in 12 cultures from mice hemizygous for Nf2 (asb-Nf2(KO3/+)) and 4 wild type counterparts (asb-Nf2(+/+)). We have found frequent inactivations of p16/Cdkn2a, p19/Arf (or P14/ARF) and p15/Cdkn2b, coinactivation of p16/Cdkn2a and p15/Cdkn2b and low rate of Trp53 mutations in both asb-Nf2(KO3/+) and asb-Nf2(+/+) mesothelioma cells. In both mouse and human mesothelioma cells, inactivation of the hortologous genes p16/Cdkn2a or P16/CDKN2A was due to deletions at the Ink4/Arf locus encompassing p19/Arf or P14/ARF, respectively. Loss of heterozygosity at the Nf2 locus was detected in 10 of 11 asb-Nf2(KO3/+) cultures and Nf2 gene rearrangement in one asb-Nf2(+/+) culture. These data show that the profile of TSG alterations in asbestos-induced mesothelioma is similar in mice and humans. Thus, the mouse mesothelioma model could be useful for human risk assessment, taking into account interindividual variations in genetic sensitivity to carcinogens.
authors.affiliation: INSERM U674, Fondation Jean Dausset-CEPH, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lecomte
authors.forename: Pascal
authors.initials: P
authors.lastname: Andujar
authors.forename: Annie
authors.initials: A
authors.lastname: Renier
authors.forename: Laurence
authors.initials: L
authors.lastname: Kheuang
authors.forename: Vincent
authors.initials: V
authors.lastname: Abramowski
authors.forename: Lucille
authors.initials: L
authors.lastname: Mellottee
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Fleury-Feith
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Jaurand
mesh_terms: D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D008654:Mesothelioma / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; D001194:Asbestos