Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study

Our plain-English summary of Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study, by S. Crovella, A.M. Bianco, J. Vuch, et al (Journal of Toxicology and Environmental Health. Part a, 2016).

The study

• Authors: S. Crovella, A.M. Bianco, J. Vuch, L. Zupin, R.R. Moura, E. Trevisan, M. Schneider, A. Brollo, E.M. Nicastro, A. Cosenzi, G. Zabucchi, V. Borelli
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2016;79(3):129-41
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The development of MPM is frequently linked to inhalation of asbestos fibers. A genetic component of susceptibility to this disease is suggested by the observation that some individuals develop MPM following lower doses of asbestos exposure, whereas others exposed to higher quantities do not seem to be affected. This hypothesis is supported also by frequent reports of MPM familial clustering. Despite the widely recognized role of iron (Fe) in cellular asbestos-induced pulmonary toxicity, the role of the related gene polymorphisms in the etiology of MPM has apparently not been evaluated. Eighty-six single-nucleotide polymorphisms (SNPs) of 10 Fe-metabolism genes were examined by exploiting formalin-fixed paraffin-embedded postmortem samples from 77 patients who died due to MPM (designated AEM) and compared with 48 who were exposed to asbestos but from died in old age of cause other than asbestos (designated AENM). All subjects showed objective signs of asbestos exposure. Three SNPs, localized in the ferritin heavy polypeptide, transferrin, and hephaestin genes, whose frequencies were distributed differently in AEM and AENM populations, were identified. For ferritin and transferrin the C/C and the G/G genotypes, respectively, representing intronic polymorphisms, were significantly associated with protection against MPM and need to be considered as possible genetic markers of protection. Similarly, the C/C hephaestin SNP, a missense variation of this multicopper ferroxidase encoding gene, may be related, also functionally, with protection against MPM. In conclusion, it is proposed that three Fe metabolism-associated genes, significantly associated with protection against development of MPM, may serve as protective markers for this aggressive tumor.

In plain English

This pilot study, from the shipbuilding town of Monfalcone in northeastern Italy, looked at whether inherited differences in genes that handle iron in the body were linked to malignant pleural mesothelioma. Using DNA from archived autopsy tissue, the authors compared 77 people with signs of asbestos exposure who died of pleural mesothelioma with 48 asbestos-exposed people who died of other causes after age 75 without developing mesothelioma. They tested 86 genetic variants in iron-metabolism genes. Three variants, in the FTH1 (ferritin), TF (transferrin) and HEPH (hephaestin) genes, were distributed differently between the two groups. For example, the HEPH C allele had a frequency of 0.01 in the mesothelioma group and 0.37 in the comparison group (odds ratio 0.02, 95% CI 0.01–0.1). The authors concluded that these iron-metabolism genes were significantly associated with susceptibility to mesothelioma. They considered the HEPH variant a possible protective factor and said the ferritin and transferrin findings need further investigation. They named the small number of subjects, caused by strict selection rules, as the study's main limitation.

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: Population-based autopsy pilot study comparing gene variants between asbestos-exposed people who died of pleural mesothelioma and asbestos-exposed people who did not develop it (genetic association study using archived autopsy tissue)
• Who was studied: Autopsies performed 1980–2000 at the Hospital of Monfalcone, Italy. The study group was 77 asbestos-exposed people who died of malignant pleural mesothelioma (AEM): 66 men and 11 women, aged 44–87, mean age 69.5. The comparison group was 48 asbestos-exposed people who died of other causes after age 75 without pleural or peritoneal mesothelioma, lung carcinoma or asbestosis (AENM): 45 men and 3 women, mean age 80.1. Three of the variants were also tested in 190 healthy blood donors from the same region.
• Exposure: Asbestos exposure, fiber type not specified, confirmed by pleural plaques and/or asbestos bodies in lung tissue. In the mesothelioma group, most men worked in shipbuilding (61%). Women were exposed at home by laundering family members' contaminated work clothes. The genetic factors studied were 86 single-nucleotide polymorphisms in iron-metabolism genes.
• Main results:
  • Only 3 of the 86 variants tested showed significant differences between the mesothelioma group and the comparison group.
  • FTH1 (ferritin) rs76059597: the C allele was counted 16 times (frequency 0.11) in the mesothelioma group (AEM) and 53 times (0.55) in the comparison group (AENM), odds ratio 0.09 (95% CI 0.05–0.18), p = 3.9 × 10^-14. The C/C genotype was found in 1 AEM subject and 23 AENM subjects.
  • TF (transferrin) rs2715631: the G allele was counted 37 times (frequency 0.24) in AEM and 51 times (0.53) in AENM, odds ratio 0.28 (95% CI 0.16–0.48), p = 5.4 × 10^-6. The G/G genotype was found in 6 AEM subjects and 17 AENM subjects (recessive model odds ratio 0.15, 95% CI 0.06–0.43).
  • HEPH (hephaestin) rs3747359: the C allele was counted 2 times (frequency 0.01) in AEM and 35 times (0.37) in AENM, odds ratio 0.02 (95% CI 0.01–0.1), p = 1.1 × 10^-13. The C/C genotype was found in 0 AEM subjects and 12 AENM subjects.
  • In the AENM comparison group, genotype frequencies did not follow the expected Hardy–Weinberg balance, while those in the mesothelioma group did. The authors attributed this to the higher frequency of the protective alleles in AENM.
  • In the 190 healthy blood donors, the HEPH variant was found only as the G allele, and no FTH1 C/C genotype was detected. Frequencies in the donors were comparable to published European (Italian Toscani) data.
  • Computer predictions found no apparent regulatory element for the FTH1 and TF variants. They found a possible damaging effect for the HEPH variant, which changes the protein.
• The authors' conclusion: The authors concluded that a significant association was found between selected iron-metabolism genes and susceptibility to develop malignant pleural mesothelioma. They said the HEPH variant may serve as a protective factor, while the FTH1 and TF observations need further investigation. They also said no functional explanation can yet be described.
• Limitations the authors state:
  • The main limitation was the low number of enrolled cases, which resulted from very restrictive inclusion criteria.
  • No functional explanation could be described: the FTH1 and TF variants have no predicted role, and little is known about hephaestin's role in the airways.
  • The exact fixation times and conditions of the archived tissue samples were not known.
  • Occupational exposure data were available for only 23 of the 48 comparison-group subjects.

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, Autopsy, Prognosis, Asbestos Exposure, Etiology, Ferritin.

Related studies

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• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Iron homeostasis in the lung following asbestos exposure — A.J. Ghio, J. Stonehuerner, et al. (2008)
• The role of iron in Libby amphibole-induced acute lung injury and inflammation — J.H. Shannahan, A.J. Ghio, et al. (2011)
• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy — V. Borelli, R.R. Moura, et al. (2015)

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