Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma

Our plain-English summary of Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma, by S.S. Murthy, J.R. Testa (Journal of Cellular Physiology, 1999).

The study

• Authors: S.S. Murthy, J.R. Testa
• Journal: Journal of Cellular Physiology
• Published: 1999;180(2):150-7
• Type of article: Review
• Cited by: 112 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure to the carcinogen asbestos is considered to be a major factor contributing to the development of most malignant mesotheliomas (MMs). We highlight the role of asbestos in MM and summarize cytogenetic and molecular genetic findings in this malignancy. The accumulation of numerous clonal chromosomal deletions in most MMs suggests a multistep process of tumorigenesis, characterized by the loss and/or inactivation of multiple tumor suppressor genes (TSGs). Cytogenetic and loss of heterozygosity (LOH) analyses of MMs have demonstrated frequent deletions of specific sites within chromosome arms 1p, 3p, 6q, 9p, 13q, 15q, and 22q. Furthermore, TSGs within two of these regions, i.e., p16/CDKN2A-p14ARF at 9p21 and NF2 at 22q12, are frequently altered in MMs. Homozygous deletion appears to be the major mechanism affecting p16/CDKN2A-p14ARF, whereas inactivating mutations coupled with allelic loss occur at the NF2 locus. Finally, recent studies have demonstrated the presence and expression of simian virus 40 (SV40) in many MMs. SV40 large T antigen has been shown to inactivate the TSG products Rb and p53, suggesting the possibility that asbestos and SV40 could act as cocarcinogens in MM. The frequent occurrence of homozygous deletions of p16/CDKN2A-p14ARF and the ability of SV40 Tag to bind TSG products suggest that perturbations of both Rb- and p53-dependent growth-regulatory pathways are critically involved in the pathogenesis of MM.

In plain English

This 1999 article by researchers at Fox Chase Cancer Center in Philadelphia was a review, not a new study. It summarized research on how asbestos may cause malignant mesothelioma and on genetic changes in these tumors, much of it from the authors' own earlier laboratory work. In one cited study of 20 mesotheliomas, 17 (85%) had lost chromosome material from region 1p21-p22, 16 (80%) from 9p, and 13 (65%) had lost a copy of chromosome 22. Another found both copies of the p16 gene deleted in 34 of 40 (85%) mesothelioma cell lines but in only five (22%) of 23 tumor samples. The authors said this gap might reflect lab culturing or normal cells mixed into tumors. Cited studies found NF2 gene mutations in 8 of 15 and 12 of 23 cell lines, and a multi-institution study found the virus SV40 in 10 of 12 mesotheliomas. The authors concluded that asbestos is a major factor in mesothelioma, that the disease involves many accumulated gene losses, and that a possible joint role of SV40 should be tested.

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: Review article summarizing earlier studies, largely the authors' own laboratory studies, on asbestos and genetic changes in malignant mesothelioma
• Who was studied: Published cytogenetic and molecular genetic studies of human malignant mesothelioma tumor specimens and cell lines. The cited studies included 20 karyotyped cases, 24 cell lines analyzed by comparative genomic hybridization, and 40 cell lines plus 23 primary tumors tested for p16. Mostly United States cases, compared with 42 Finnish cases.
• Exposure: Asbestos in general, including chrysotile and the amphibole fibers crocidolite, amosite and tremolite. Simian virus 40 (SV40) was discussed as a possible cofactor. No exposure doses were analyzed.
• Main results:
  • In the authors' earlier karyotyping study of 20 mesothelioma cases, 17 of 20 (85%) had losses from region 1p21-p22, 16 of 20 (80%) had losses involving 9p, and 13 (65%) had monosomy 22.
  • In the authors' comparative genomic hybridization study of 24 mesothelioma cell lines, underrepresentation of 22q was seen in 14 of 24 (58%).
  • In a cited study of 40 cell lines and 23 primary tumors, homozygous deletions of p16 were found in 34 (85%) of the cell lines but only five (22%) of the tumor specimens.
  • NF2 mutations were found in 8 of 15 (53%) cell lines in one cited study and in 12 of 23 new mesothelioma cell lines in a later one. In the later work, 18 of 25 cell lines (72%) showed allelic losses near the NF2 locus.
  • In a multi-institutional study, SV40 sequences and SV40 Tag expression were found in 10 of 12 (83%) mesotheliomas tested.
  • In the same study, asbestos fibers were found in five of seven (71%) corresponding lung tissues. The two cases with no fibers both tested positive for SV40 DNA.
• The authors' conclusion: The authors concluded that asbestos exposure is a major factor in the development of malignant mesothelioma. They considered crocidolite the most oncogenic type, with the oncogenicity of chrysotile still debated. They said mesothelioma results from many accumulated acquired genetic events, mainly deletions. They also said a possible cocarcinogenic interaction between SV40 and asbestos should be carefully tested in future investigations.
• Limitations the authors state:
  • The authors noted that primary tumor samples often contain normal cells, which may hide gene deletions. The much higher rate of p16 changes in cell lines might instead be an artifact of culturing.
  • The authors stated that the order in which these genetic events occur cannot be determined because there are no data from early stages of the disease.

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, Malignant Mesothelioma, Tumorigenesis, CDKN2A, Homozygous Deletion, SV40.

Related studies

• Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma — C. Lecomte, P. Andujar, et al. (2005)
• Recurring loss involving chromosomes 1, 3, and 22 in malignant mesothelioma: possible sites of tumor suppressor genes — W.L. Flejter, F.P. Li, et al. (1989)
• LATS2 is a tumor suppressor gene of malignant mesothelioma — H. Murakami, T. Mizuno, et al. (2011)
• 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)
• Analysis of chromosomal alterations induced by asbestos and ceramic fibers — E. Dopp, D. Schiffmann (1998)
• Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis — J.F. Lechner, J. Tesfaigzi, et al. (1997)

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