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

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 as involved in asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM have been reported, to date the impact of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron homeostasis are hallmarks of asbestos exposure affecting the lung tissue, in this study we aimed at investigating the association between iron-metabolism and inflammasome gene variants and susceptibility to develop LC, by comparing an asbestos exposed population affected by LC with an "asbestos-resistant exposed population". We employed a retrospective approach same as our previous autopsy-based pilot study and we also replicated our previous findings on MPM by repeating the analysis in a novel cohort of autoptic samples. We confirmed the protective role of HEPH coding SNP but also of the two non-coding SNP, either in FTH1 or in TF, in a novel cohort of mesothelioma exposed individuals and we found the same protective genetic variants in a cohort of LC exposed individuals, from the same geographic area of MPM subjects, suggesting a common "protection profile". 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" would be needed to broaden our knowledge of the genetic landscape causative of MPM and LC.

The Molecular Basis of Malignant Pleural Mesothelioma

“…Although there was no association between the number of ABs and most of the selected genes, the frequency of the single nucleotide polymorphism (SNP) rs12150220 A/T (17p13.2) in the NLRP1 gene correlated with a significantly lower number of ABs, suggesting that NLRP1 inflammasome may contribute in the development of lung ABs. A subsequent analysis by the same group found no association between polymorphisms in NLRP1 or NLRP3 and susceptibility to MPM in asbestos-exposed individuals 24 .…”

Molecular Signatures Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy

“…trascriptome, proteome), have been used to assess toxicities associated to radiotherapy in lung/pleural cancer. It is important to note that population-based studies can be difficult to translate into clinical care, especially in the case of a multifactorial disease such as MPM in which surgical and radiotherapy procedures are not standardized (12) and little is known about the genetic bases leading to augmented susceptibility to this disease (42)(43)(44).…”

The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value

“…The role played by HEPH in iron metabolism in lung is still poorly characterized, and so is its possible contribution to lung carcinogenesis and growth. We recently identified a singlenucleotide polymorphism within HEPH gene, leading to a missense variation of this multicopper ferroxidase, which confers protection against asbestos-dependent malignant pleural mesothelioma and lung carcinoma in exposed subjects (24,25). Moreover, in breast cancer HEPH expression has been shown to be down-regulated by the histone methyltransferase G9a, leading to changes in iron homeostasis that burst cancer growth (26).…”