Exploring environmental causes of altered ras effects: fragmentation plus integration?

Our plain-English summary of Exploring environmental causes of altered ras effects: fragmentation plus integration?, by M. Porta, D. Ayude, J. Alguacil, et al (Molecular Carcinogenesis, 2003).

The study

• Authors: M. Porta, D. Ayude, J. Alguacil, M. Jariod
• Journal: Molecular Carcinogenesis
• Published: 2003;36(2):45-52
• Type of article: Review
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mutations in ras genes are the most common abnormality of oncogenes in human cancer and a major example of activation by point mutation. Experimental and epidemiological studies support the notion that Ki-ras activation and expression may be chemically related. We discuss the potential role of several environmental compounds in the induction or promotion of ras mutations in humans, with a focus on exocrine pancreatic cancer, the human tumor with the highest prevalence at diagnosis of Ki-ras mutations. Organochlorine compounds, organic solvents, and coffee compounds may play an indirect role in causing Ki-ras mutations, rather than as direct inducers of the mutations. Although for some organochlorine compounds the induction of point mutations in ras oncogenes cannot be excluded, it seems more likely that the effects of these compounds are mediated through nongenomic or indirectly genotoxic mechanisms of action. Organic solvents also may act via enzymatic induction of ras mutagens or by providing a proliferation advantage to ras-mutated cell clones. In exocrine pancreatic cancer, caffeine, other coffee compounds, or other factors with which coffee drinking is associated could modulate Ki-ras activation by interfering with DNA repair, cell-cycle checkpoints, and apoptosis. Asbestos, cigarette smoking, and some dietary factors also may be involved in the initiation or the promotion of Ki-ras mutations in lung and colon cancers. Further development of the mechanistic scenarios proposed here could contribute to a meaningful integration of biological, clinical, and environmental knowledge on the causes of altered ras effects.

Copyright 2003 Wiley-Liss, Inc.

In plain English

This article, labelled a "working hypothesis" paper, was a discussion piece rather than a new study. It reported no new data. The authors discussed how environmental chemicals might be involved in causing or promoting mutations in the Ki-ras gene, focusing on exocrine pancreatic cancer. They summarized their own earlier studies of pancreatic cancer patients. Compared with patients whose tumors lacked a Ki-ras mutation, patients whose tumors carried one had significantly higher blood levels of DDT, DDE and some PCBs, were more likely to have been occupationally exposed to organic solvents, and were significantly more likely to be regular coffee drinkers. The authors argued that these exposures, if their effects are real, more likely act indirectly than by directly causing the mutations. Examples were helping mutated cells grow or interfering with DNA repair. Asbestos appeared only briefly: citing other researchers' work, the authors noted that occupational asbestos exposure has been associated with Ki-ras mutations in patients with lung adenocarcinoma. The authors acknowledged that their proposed scenarios may be too broad, unspecific or even speculative.

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: Working hypothesis / narrative discussion paper reviewing the authors' earlier studies and other published research; no new data
• Who was studied: No study population of its own; the discussion focused on exocrine pancreatic cancer, drawing on the authors' earlier studies of patients with this cancer
• Exposure: Organochlorine compounds (DDT, DDE, PCBs), organic solvents and coffee compounds, mainly. Asbestos, cigarette smoking and dietary factors were mentioned briefly in relation to lung and colon cancers.
• Main results:
  • The authors summarized their earlier finding that exocrine pancreatic cancer cases with a Ki-ras mutation had significantly higher serum concentrations of DDT, DDE and some PCBs than cases with wild-type Ki-ras.
  • The authors summarized their earlier finding that patients with Ki-ras-mutated pancreatic tumors were more likely to have been occupationally exposed to organic solvents than patients with wild-type Ki-ras.
  • The authors summarized their earlier finding that pancreatic tumors of regular coffee drinkers were significantly more likely to carry a Ki-ras mutation than those of patients who were not regular coffee drinkers, with a dose-response relationship.
  • The authors argued that the effects of organochlorines, organic solvents and coffee compounds, if real, are more likely mediated through nongenomic or indirectly genotoxic mechanisms than through directly causing Ki-ras mutations.
  • Citing other researchers' studies (not their own), the authors noted that cigarette smoking and occupational asbestos exposure have been associated with Ki-ras mutations in patients with lung adenocarcinoma.
• The authors' conclusion: The authors concluded that further development of their proposed mechanistic scenarios could contribute to integrating biological, clinical and environmental knowledge on the causes of altered ras effects.
• Limitations the authors state:
  • The authors acknowledged that their proposed interpretive scenarios may be too broad, unspecific or even speculative.
  • The authors stated that many pieces of knowledge may still be missing for a meaningful integration.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Colorectal Cancer.

Related studies

• Occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons and other agents and K-ras activation in human exocrine pancreatic cancer — J. Alguacil, M. Porta, et al. (2003)
• p53 and ras gene mutations in lung cancer: implications for smoking and occupational exposures — K. Husgafvel-Pursiainen, M. Ridanpää, et al. (1995)
• Lung cancer and past occupational exposure to asbestos. Role of p53 and K-ras mutations — K. Husgafvel-Pursiainen, A. Karjalainen, et al. (1999)
• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)
• A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design — F. Passiglia, P. Bironzo, et al. (2021)
• Analysis of K-ras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos — Z. Ni, Y. Liu, et al. (2000)

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