Role of gene and chromosomal mutations in cell transformation

Our plain-English summary of Role of gene and chromosomal mutations in cell transformation, by J.C. Barrett, D.G. Thomassen, T.W. Hesterberg (Annals of the New York Academy of Sciences, 1983).

The study

• Authors: J.C. Barrett, D.G. Thomassen, T.W. Hesterberg
• Journal: Annals of the New York Academy of Sciences
• Published: 1983;407:291-300
• Type of article: Review
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To understand the role of mutagenesis in carcinogenesis fully, we must consider all types of mutations including gene, chromosomal, and gene-number mutations and all changes involved in the progressive development of neoplastic cells. We have found that certain known human carcinogens (i.e., DES and asbestos), which were classified as epigenetic carcinogens based on gene-mutation assays, have mutational activity at the chromosomal level that correlates with their ability to induce cell transformation. This should caution against classification of chemicals as genotoxic or epigenetic without a complete understanding of their mechanism of action. Furthermore, our studies indicate that more than gene-mutation assays is needed for carcinogen testing. In particular, chromosomal changes induced by chemicals, both aberrations and aneuploidy, need to be carefully assessed. In addition, the role of all types of mutation in the overall process of neoplastic transformation needs to be determined. This can only be examined by studying each individual change involved in neoplastic progression. Thus, any attempt to assess a chemical's carcinogenic potential should consider not only all types of mutational changes but both early and late changes involved in neoplastic transformation.

In plain English

This article reviewed the authors' own laboratory studies on whether substances that cause cell transformation, an early pre-cancerous change in cultured cells, also cause mutations. The work used mainly Syrian hamster embryo cells and compared gene mutations with chromosome changes. The text does not name the type of asbestos tested or give doses. The authors reported that asbestos produced a dose-dependent increase in transformation of these cells, and that long, thin fibers worked better than short, thick ones. Under the same conditions, asbestos caused no detectable gene mutations at the two genes tested. Fibers entered cells within 2 hours and by 24 hours collected around the nucleus. By then some dividing cells had abnormal chromosome numbers or damaged chromosomes. Diethylstilbestrol (DES) also transformed the cells without detectable gene mutations, but caused only abnormal chromosome numbers, not damaged chromosomes. The authors concluded that asbestos and DES act at the chromosome level and cautioned against calling them non-genetic carcinogens on the basis of gene-mutation tests alone. They said how these chromosome changes relate to transformation still needed study.

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 of the authors' own laboratory (cell-culture) studies on mutation and cell transformation
• Who was studied: Cultured Syrian hamster embryo cells (some work with MNNG also used rat tracheal epithelial cells); laboratory at the National Institute of Environmental Health Sciences, North Carolina; number of experiments not given
• Exposure: Asbestos (fiber type not specified in the text), compared with 2-aminopurine, 6-N-hydroxylaminopurine, diethylstilbestrol, MNNG and benzo[a]pyrene; doses not given
• Main results:
  • Asbestos caused a dose-dependent induction of neoplastic transformation in Syrian hamster embryo cells
  • In Syrian hamster embryo cells, long, thin asbestos fibers were more effective at transforming cells than short, thick fibers
  • Under conditions that transformed the cells, asbestos caused no detectable gene mutations at the HPRT or Na+/K+-ATPase genes
  • Asbestos was taken up by the cells 2 hours after exposure; by 24 hours many fibers were in the region around the nucleus
  • By 24 hours after asbestos treatment, some dividing cells had abnormal chromosome numbers (aneuploid or polyploid) and chromosome aberrations
  • Under conditions that transformed the cells, DES caused no measurable gene mutation at the HPRT or Na+/K+-ATPase genes
  • DES, at concentrations that transformed the cells, produced aneuploidy in up to 20% of cells but no chromosome aberrations
  • Of the compounds discussed, DES induced only aneuploidy, while the others, including asbestos, induced both aneuploidy and chromosome aberrations
  • With MNNG, the frequency of transformation was about 100 times the frequency of gene mutations
• The authors' conclusion: The authors concluded that DES and asbestos, classed as epigenetic carcinogens on the basis of gene-mutation tests, have mutational activity at the chromosome level that correlates with their ability to transform cells, and that carcinogen testing needs more than gene-mutation assays
• Limitations the authors state:
  • How the chromosome changes caused by asbestos relate to neoplastic transformation was not yet known
  • Morphologically transformed hamster cells are not themselves tumor-forming
  • The relationship between the early changes seen in cultured cells and events in the living body is unknown
  • The authors could not determine whether one type of chromosomal mutation matters more than another

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Carcinogenic.

Related studies

• Crocidolite induces cell transformation and p53 gene mutation in BALB/c-3T3 cells — F. Lin, Y. Liu, et al. (2000)
• Metsovo-tremolite asbestos fibres: in vitro effects on mutation, chromosome aberration, cell transformation and intercellular communication — K. Athanasiou, S.H. Constantopoulos, et al. (1992)
• Asbestos promotes morphological transformation and elevates expression of a gene family invariably induced by tumor promoters in C3H/10T1/2 cells — C.L. Parfett, R. Pilon, et al. (1996)
• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity — M. Bocchetta, I. Di Resta, et al. (2000)
• Promotion of morphological transformation by Di-n-butyltin dichloride in C3H/10T1/2 cells: prediction by prior expression of tumour promoter-responsive genes — C.L. Parfett, T. Marquardt, et al. (2000)
• Use of the orthogonal design method to study the synergistic effects of asbestos fibres and 12-O-tetradecanoylphorbol-13-acetate (TPA) in the BALB/3T3 cell transformation system — Y.P. Lu, C. Lasne, et al. (1988)

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