Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma

Our plain-English summary of Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma, by C. Lecomte, P. Andujar, A. Renier, et al (Cell Cycle, 2005).

The study

• Authors: C. Lecomte, P. Andujar, A. Renier, L. Kheuang, V. Abramowski, L. Mellottee, J. Fleury-Feith, J. Zucman-Rossi, M. Giovannini, M.C. Jaurand
• Journal: Cell Cycle
• Published: 2005;4(12):1862-9
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study compared genetic changes in mesothelioma cells from mice and from people. The mouse cells came from 15 cultures grown from tumoral ascites (tumor-containing abdominal fluid) in crocidolite-exposed mice. Eleven of these mice carried only one working copy of the Nf2 gene and 4 were normal (wild type). Twelve cultures from human malignant mesothelioma cases were also tested. The authors looked for damage to tumor suppressor genes, which normally restrain cell growth. In all but 3 of the 15 mouse cultures, a region containing the p16/Cdkn2a and p19/Arf genes was missing. Trp53 changes were less common: one culture had two mutations and another showed a pattern suggesting gross chromosomal alteration. Combining four new cultures with seven from the authors' earlier study, the normal Nf2 copy was lost in 10 of 11 cultures from Nf2-deficient mice. All 12 human cultures had P16/CDKN2A deletions and lacked p16 and p14 proteins, and 3 of the 12 had TP53 mutations. The authors concluded that the asbestos-induced mouse tumors showed the most common genetic changes found in human mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory genetic study of mesothelioma cell cultures from asbestos-exposed mice (genetically modified and wild type) and from human mesothelioma cases
• Who was studied: 15 mouse mesothelioma cell cultures from tumoral ascites of 11 asbestos-exposed Nf2KO3/+ mice (one working Nf2 copy) and 4 asbestos-exposed wild type mice (FVB/N background), plus 12 human cell cultures from confirmed malignant mesothelioma cases
• Exposure: Mice exposed to crocidolite asbestos. The introduction describes the model as intraperitoneal inoculation, but no dose is given in this article. The human patients' exposures are not described.
• Main results:
  • In the mouse cultures, the three Ink4a locus exons (p16/Cdkn2a and p19/Arf) were lost in all but 3 of 15 cultures (759, 762 and 453 kept them).
  • p15Ink4b protein was detected only in the three mouse cultures that expressed p16Ink4a.
  • A normal Trp53 restriction pattern was seen in 14 of 15 mouse cultures. Culture 453 showed a pattern suggesting gross chromosomal alteration.
  • Mouse culture 759 had two Trp53 mutations in exon 8. Its yeast functional (FASAY) test gave 98% red colonies, a result associated with p53 mutation.
  • Loss of the normal Nf2 copy was found in 10 of 11 cultures from asbestos-exposed Nf2KO3/+ mice: 4 of 4 new cultures plus 6 of 7 reported earlier. One culture from a wild type mouse (453) showed Nf2 gene rearrangement.
  • In all 12 human mesothelioma cultures, P16/CDKN2A deletions were found and p16INK4A and p14ARF proteins were not detected.
  • TP53 mutations were found in 3 of the 12 human cultures (BT, RV, QR). Their FASAY results were 95%, 99.2% and 99.3% red colonies.
• The authors' conclusion: The authors concluded that asbestos-induced mesothelioma in these Nf2 mice shows the most common genetic alterations found in human malignant mesothelioma. They suggested that NF2 hemizygosity (having only one working copy) may be a susceptibility factor for asbestos exposure.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Tumor Suppressor Gene, Mesothelioma, Malignant Mesothelioma, Ascites, CDKN2A.

Related studies

• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Clinico-pathological features and somatic gene alterations in refractory ceramic fibre-induced murine mesothelioma reveal mineral fibre-induced mesothelioma identities — P. Andujar, C. Lecomte, et al. (2007)
• Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma — S.S. Murthy, J.R. Testa (1999)
• Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis — C.W. Menges, Y. Kadariya, et al. (2014)
• Gene expression profiles reveal increased mClca3 (Gob5) expression and mucin production in a murine model of asbestos-induced fibrogenesis — T. Sabo-Attwood, M. Ramos-Nino, et al. (2005)
• Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus — C. Walker, Y.T. Ahn, et al. (1996)

Browse return to medical research.