Mesothelioma Driver Genes, Ferroptosis, and Therapy

Our plain-English summary of Mesothelioma Driver Genes, Ferroptosis, and Therapy, by E. Felley-Bosco, S.G. Gray (Frontiers in Oncology, 2019).

The study

• Authors: E. Felley-Bosco, S.G. Gray
• Journal: Frontiers in Oncology
• Published: 2019;9:1318
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

In plain English

This was a short opinion article, not a new study. The authors wrote it to add to an editorial by Fennell. They discussed how genes often altered in mesothelioma (NF2, BAP1 and CDKN2A) may relate to ferroptosis, a type of iron-dependent regulated cell death. They drew on research by others, the mesothelioma TCGA database, and data from their own previously published model of mesothelioma development. In that model, comparing tumors with inflamed precancerous lesions, they reported a 1.4-fold increase in Acsl4 expression, a 74% decrease in Gpx4, a 91% decrease in Msrb2, and a 4.7-fold increase in Slc7a11, each described as significant. According to TCGA data, alterations in both the NF2 and BAP1 pathways occur in a significant fraction of malignant pleural mesothelioma (MPM) patients. The authors suggested that such tumors might be more resistant to ferroptosis, but stated that functional studies are necessary to verify this hypothesis. They also discussed drugs that affect ferroptosis, such as sorafenib and erastin, and proposed checking whether patients who responded to sorafenib in earlier trials had a disrupted NF2/Hippo pathway.

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: Opinion article responding to an editorial. It draws on published studies, the TCGA database, and gene-expression data from the authors' own previously published model of mesothelioma development.
• Who was studied: Tumors and inflamed precancerous lesions from the authors' own previously published model of mesothelioma development (details not given in this article), plus malignant pleural mesothelioma (MPM) data from the TCGA database (numbers not given).
• Exposure: No exposure was studied directly. The article concerns the mesothelioma driver genes NF2, BAP1 and CDKN2A and ferroptosis. It mentions a rat study by another group (Nagai et al.) in which iron chelation did not prevent mesothelioma after exposure to asbestos fibers.
• Main results:
  • In the authors' model, tumors compared with inflamed precancerous lesions showed a significant 1.4-fold increase in Acsl4 expression (p = 0.008971, FDR = 0.0145).
  • In the same comparison of tumors with inflamed precancerous lesions, Gpx4 expression fell significantly by 74% (p = 6.28E-22, FDR = 8.19E-21) and Msrb2 expression by 91% (p = 1.38E-88, FDR = 4.95E-86).
  • In the model tumors, Slc7a11 showed a significant 4.7-fold upregulation (p = 0.004227, FDR = 0.007263), which the authors described as consistent with loss of one BAP1 allele.
  • According to TCGA data, alterations in both the NF2 and BAP1 pathways occur in a significant fraction of MPM patients. No figure is given in the text.
• The authors' conclusion: The authors concluded that their observations suggest tumors with alterations in both the NF2 and BAP1 pathways might be more resistant to ferroptosis. They stated that functional studies are needed to verify this hypothesis.
• Limitations the authors state:
  • The authors stated that their hypothesis about ferroptosis resistance needs to be verified by functional studies.
  • The authors noted that it has not been established whether mesothelioma cells can undergo ferroptosis in a living body (in vivo).

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

• The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy — S. Toyokuni (2016)
• The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism — S. Chang, S. Yim, et al. (2019)
• Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)
• Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas — N.C. Campanella, E.C. Silva, et al. (2020)
• BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma — L. Bisceglia, F. Morani, et al. (2024)
• New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents — A.K. Nowak, R.A. Lake, et al. (2002)

Browse more research in Frontiers in Oncology, or return to medical research.