Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma

Our plain-English summary of Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma, by D. Jean, E. Thomas, E. Manié, et al (The American Journal of Pathology, 2011).

The study

• Authors: D. Jean, E. Thomas, E. Manié, A. Renier, A. de Reynies, C. Lecomte, P. Andujar, J. Fleury-Feith, F. Galateau-Sallé, M. Giovannini, J. Zucman-Rossi, M.H. Stern, M.C. Jaurand
• Journal: The American Journal of Pathology
• Published: 2011;178(2):881-94
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an aggressive tumor with a poor prognosis mainly linked to past asbestos exposure. Murine models of MM based on fiber exposure have been developed to elucidate the mechanism of mesothelioma formation. Genomic alterations in murine MM have now been partially characterized. To gain insight into the pathophysiology of mesothelioma, 16 murine and 35 human mesotheliomas were characterized by array-comparative genomic hybridization and were screened for common genomic alterations. Alteration of the 9p21 human region, often by biallelic deletion, was the most frequent alteration in both species, in agreement with the CDKN2A/CDKN2B locus deletion in human disease and murine models. Other shared aberrations were losses of 1p36.3-p35 and 13q14-q33 and gains of 5p15.3-p13 regions. However, some differences were noted, such as absence of recurrent alterations in mouse regions corresponding to human chromosome 22. Comparison between altered recurrent regions in asbestos-exposed and non-asbestos-exposed patients showed a significant difference in the 14q11.2-q21 region, which was also lost in fiber-induced murine mesothelioma. A correlation was also demonstrated between genomic instability and tumorigenicity of human mesothelioma xenografts in nude mice. Overall, these data show similarities between murine and human disease, and contribute to the understanding of the influence of fibers in the pathogenesis of mesothelioma and validation of the murine model for preclinical testing.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study compared the genetic changes in mesothelioma cells from mice and from patients. The authors examined 16 cell cultures from mice, 12 of them genetically modified, that had developed mesothelioma after asbestos or refractory ceramic fibers were injected into the abdominal cavity. They also examined 35 cultures from human mesothelioma patients, using array-based comparative genomic hybridization, a test that detects gained and lost chromosome regions. Interviews showed asbestos exposure in 24 patients, possible exposure in two and no exposure in eight. In both species, the most frequently altered region included the CDKN2A and CDKN2B genes. Mouse tumors showed no recurrent changes in regions matching human chromosome 22. Loss of the 14q11.2–q21 region reached 46% in asbestos-exposed patients and 0% in unexposed patients, and matching mouse regions were altered in 44% of mouse tumors. Human cells with more chromosome breakpoints were more likely to grow as tumors in mice. The authors concluded that mouse and human mesothelioma share common genomic alterations. They suggested that the 14q region might be a target of mineral fibers.

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 genomic comparison of cultured mouse and human mesothelioma cells using array-comparative genomic hybridization, plus tests of whether the human cells formed tumors when injected into immunocompromised (nude) mice
• Who was studied: 16 mouse mesothelioma cell cultures, taken from abdominal tumor fluid of 12 Nf2-gene-modified mice and 4 wild-type mice. 35 human malignant mesothelioma cell cultures from patients: 29 male and 6 female, mean age 63 (men) and 69 (women). The article does not state dates or the tumor site (pleural or peritoneal) for the patients.
• Exposure: Mice: asbestos or refractory ceramic fibers injected into the peritoneal cavity in earlier experiments; specific asbestos fiber types are not named. Patients: asbestos exposure was assessed by face-to-face questionnaire covering occupational, domestic and environmental exposure. Exposure was ascertained in 24, possible in 2 and not found in 8, with no data for 1.
• Main results:
  • Mouse mesotheliomas had an average of 10.7 altered chromosomes (autosomes) per tumor, range 4 to 18.
  • Human mesotheliomas had a mean of 13.8 altered chromosomes (autosomes) per tumor, range 1 to 21.
  • The lost region with the highest frequency was shared by both species: human 9p24–p13 in 91% of human cultures, and the corresponding mouse region 4qC3–C5 in 81% of mouse cultures.
  • The 9p21 region, containing the CDKN2A and CDKN2B genes, showed the highest alteration frequency in both species.
  • Homozygous (both-copy) deletions in the 9p21 region were found in 63% of human and 40% of mouse mesotheliomas.
  • Mouse tumors showed no recurrent alterations in the regions corresponding to human chromosome 22.
  • Gene mutation rates did not differ significantly between human and mouse mesotheliomas. TP53 mutations were found in 20% of human and 25% of mouse mesotheliomas.
  • Of 32 human cultures tested in immunocompromised mice, 23 grew tumors. A higher number of chromosome breakpoints was statistically associated with tumor growth (P value printed as 0.031; the comparison sign is lost in the text).
  • Loss in the 14q11.2–q21 region had a maximum frequency of 46% in asbestos-exposed patients (24 cases) and 0% in non-asbestos-exposed patients (8 cases), P value printed as 0.03.
  • In the fiber-induced mouse tumors, the mouse regions matching human 14q11.2–q21 were altered in 44%.
  • The authors suggested that the 14q11.2–q21 region might be a target of mineral fibers.
  • Patterns of alteration by tissue subtype (epithelioid vs sarcomatoid) showed no similarity between human and mouse tumors.
• The authors' conclusion: The authors concluded that, despite certain differences, mouse and human mesothelioma share common genomic alterations.
• Limitations the authors state:
  • Differences by tissue subtype were not statistically significant, partly because the statistical analysis had low power.
  • Differences between species could reflect technical issues, such as the different resolution of the human and mouse arrays, as well as species differences.
  • Comparing NF2 alterations between species was difficult because most mouse cultures came from Nf2-modified mice.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Asbestos Exposure, Mesothelioma, CDKN2A.

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