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

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.

ORCID

Violetta Borelli

http://orcid.org/0000-0002-8166-3513

Acknowledgments

We thank Dr. Claudio Bianchi for his valued help in the data collection process, and Maurizio Bolteri and all the staff of the Monfalcone’s Hospital Pathological Anatomy Unit for their valuable technical assistance. We thank also Dr. Alessandra Knowles for her assistance in revising the article and Fondazione Carlo e Dirce Callerio ONLUS for the technical support.

Additional information

Funding

This work was supported by Associazione Esposti Amianto di Monfalcone and by a grant from the University of Trieste, FRA 2011 (Local Research Grant).