Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes

Our plain-English summary of Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes, by F. Celsi, S. Crovella, R.R. Moura, et al (Journal of Toxicology and Environmental Health. Part a, 2019).

The study

• Authors: F. Celsi, S. Crovella, R.R. Moura, M. Schneider, F. Vita, L. Finotto, G. Zabucchi, P. Zacchi, V. Borelli
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2019;82(20):1088-1102
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an "asbestos-resistant exposed population". A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC "genetic signature" may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.

In plain English

This was a retrospective genetic study of archived autopsy tissue from the Monfalcone area of north-east Italy, where most subjects had worked in shipbuilding. The authors compared 52 asbestos-exposed people who had pleural mesothelioma and 57 asbestos-exposed men who had lung cancer (autopsies 2009 to 2015) with 48 asbestos-exposed people who died of other causes after age 75 without these cancers (autopsies 1980 to 2000). Exposure was established from pleural plaques and/or asbestos bodies in lung tissue. DNA was tested for variants in three iron-metabolism genes (HEPH, TF, FTH1) and two inflammation genes (NLRP1, NLRP3). For each iron-gene variant, the allele studied was more common in the comparison group than in either cancer group. For example, for the HEPH C allele the odds ratio was 0.06 (95% CI 0.003 to 0.3) for mesothelioma and 0.03 (95% CI 0.005 to 0.12) for lung cancer. The authors read these results as a possible protective association. The NLRP1 and NLRP3 variants showed no significant differences. The authors concluded that the study confirms their earlier mesothelioma findings and extends them to lung cancer. They noted the small sample, the few variants tested and badly degraded DNA, and said the results should be considered cautiously.

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: Retrospective autopsy-based genetic association study comparing asbestos-exposed people with cancer to asbestos-exposed people without it
• Who was studied: Autopsy cases from Monfalcone Hospital, Monfalcone area, north-east Italy. 52 asbestos-exposed people with pleural mesothelioma (46 men, 6 women) and 57 asbestos-exposed men with lung cancer, both autopsied 2009 to 2015. The comparison group was 48 asbestos-exposed people (45 men, 3 women) autopsied 1980 to 2000 who died of other causes after age 75 without mesothelioma or lung cancer. DNA was taken from archived formalin-fixed heart tissue.
• Exposure: Asbestos exposure was established at autopsy by pleural plaques and/or asbestos bodies in lung sections. Most subjects with job histories worked in the shipyard or shipyard-related jobs, and four mesothelioma cases had domestic (take-home) exposure. The authors state possible mixed exposure to chrysotile and amphiboles. Genetic variants tested: HEPH rs3747359, TF rs2715631, FTH1 rs76059597, NLRP1 rs12150220 and rs6502867, and NLRP3 rs35829419 and rs10754558.
• Main results:
  • HEPH rs3747359: the C allele was more frequent in the comparison group than in the mesothelioma group (OR = 0.06, 95% CI 0.003 to 0.3; p = 8.5 x 10 to the minus 5). The authors described this as possibly associated with protection.
  • HEPH rs3747359: the C allele was more frequent in the comparison group than in the lung cancer group (OR = 0.03, 95% CI 0.005 to 0.12; p = 6.1 x 10 to the minus 12).
  • TF rs2715631: the G allele was more frequent in the comparison group than in the mesothelioma group (OR = 0.22, 95% CI 0.12 to 0.47; p = 3.5 x 10 to the minus 6).
  • TF rs2715631: the G allele was more frequent in the comparison group than in the lung cancer group (OR = 0.15, 95% CI 0.07 to 0.31; p = 3.9 x 10 to the minus 9).
  • FTH1 rs76059597: the C allele was less frequent in the mesothelioma group than in the comparison group (OR = 0.1, 95% CI 0.05 to 0.22).
  • FTH1 rs76059597: the C allele was less frequent in the lung cancer group than in the comparison group (OR = 0.13, 95% CI 0.07 to 0.25).
  • The comparison group was not in Hardy-Weinberg equilibrium for the FTH1 variant. It was in equilibrium for all other variants.
  • NLRP1 rs6502867: no statistically significant differences in allele distribution, either between the mesothelioma group and the comparison group or between the lung cancer group and the comparison group.
  • NLRP1 rs12150220: no marked differences between the mesothelioma group and the comparison group.
  • NLRP3 rs10754558 and rs35829419: no significant differences, either for the mesothelioma group or for the lung cancer group compared with the comparison group.
  • In the lung cancer group, smoking status was known for 48 of 57 men: 46 were smokers and 2 were nonsmokers.
• The authors' conclusion: The authors concluded that the study confirms their earlier iron-gene findings in asbestos-exposed people with mesothelioma and extends them to people with lung cancer. They hypothesized a common mechanism that needs further investigation.
• Limitations the authors state:
  • Only a limited number of genetic variants were analyzed, in a small sample.
  • The DNA from formalin-fixed archive tissue was extremely poor and degraded.
  • The approach does not allow comparison with recent genome-wide study results, so the authors said the observations should be considered cautiously.
  • The findings have not appeared in large genome-wide studies, and functional studies are needed to confirm them.
  • There were too few nonsmokers to analyze the lung cancer group by smoking habit.
  • Small numbers prevented analysis by tumor histological subtype.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Lung Cancer, Asbestos Exposure, Inflammation, Carcinogenesis, Genotoxicity, Autopsy.

Related studies

• A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma — S. Crovella, R.R. Moura, et al. (2018)
• Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study — S. Crovella, A.M. Bianco, et al. (2016)
• Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers — S. Crovella, R.R. Moura, et al. (2022)
• The role of iron in Libby amphibole-induced acute lung injury and inflammation — J.H. Shannahan, A.J. Ghio, et al. (2011)
• Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice — L. Pascolo, G. Zabucchi, et al. (2016)
• Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study — G. Matullo, S. Guarrera, et al. (2013)

Browse more research in Journal of Toxicology and Environmental Health. Part a, or return to medical research.