**4. Radon**

*Oncogenes and Carcinogenesis*

At the epigenetic level, alterations affecting tumor suppressor genes have been observed in lung cancer cases associated with asbestos exposure, including those in the promoter regions of *RASSF1A* and *CDKN2A* (p16) [82]. Additionally, a genome-wide DNA methylation study identified differentially methylated CpGs in regions nearby the transcription start site of genes such as *NPTN, NRG2, GLT25D2*

The effect of asbestos on micro RNA (miRNA) expression has been also investigated. miRNAs are short (~22 nucleotide) RNA transcripts that negatively regulate gene expression through direct interaction with mRNAs. Interestingly, the overexpression of miR-148b has been described in multiple independent studies. This miRNA was part of an asbestos-related signature in lung tumors, also composed of seven other overexpressed (miR-374a, miR-24-1\*, let-7d, Let-7e, miR-199b-5p, miR-331-3p, and miR-96) and five miRNAs with decreased expression in tumors (miR-939, miR-671-5p, miR-605, miR-1224-5p, and miR-20) [84]. Additionally, miR-148b was found to be overexpressed in asbestos-related lung cancer compared to tumors in non-exposed individuals, and three of its targets (*GADD45A, LTBP1*

Despite the known genetic and epigenetic abnormalities resulting from asbestos

While the oncogenic effects of asbestos have been extensively established, recent evidence indicates that non-asbestos fibers, both natural and synthetic in nature can also cause thoracic cancers. Non-asbestos mineral (natural) fibers include erionite and fluoro-edenite, among others. Erionite is a naturally occurring fibrous mineral that shares some physical properties with asbestos, although it is less widespread. In fact, it has been shown that erionite is a more potent carcinogen in causing malignant mesothelioma [87, 88]. Erionite activates the NLR family pyrin domain containing 3 (*NLRP3, NALP3*) inflammasome, inducing the transcription and production of cytokines critical to cancer initiation [89]. On the other hand, Fluoro-edenite (originating from volcanic activity) can induce ROS that result in DNA damage and increase in lactic dehydrogenase release (a damage and toxicity marker) in human lung adenocarcinoma (A549) and monocyte-macrophage (J774)

exposure, a relatively small proportion of exposed individuals develop thoracic malignancies (mesothelioma or lung cancer). It has been hypothesized that specific genetic variants may confer increased risk of developing asbestos-related diseases [85]. Thus, recent studies have investigated the association between genomic variants and risk of lung cancer following asbestos exposure. In a genome-wide association study (GWAS) performed in the Texas lung cancer GWAS dataset, the authors did not find statistical evidence for gene-asbestos interaction in the etiology of lung cancer [86]. However, the Fas signaling pathway (regulation of tissue homeostasis in the immune system by inducing apoptosis) was identified as the most significant pathway associated with asbestos exposure in the etiology of lung cancer. Another study identified three single nucleotide polymorphisms (SNPs) in the *MIRLET7BHG* (*MIRLET7B* host gene located at 22q13.31) significantly associated with increased lung cancer risk among individuals exposed to asbestos [36]. The identification of risk variants linked with asbestos-related lung cancer is a challenging task. Sample sizes for asbestos-related lung cancer cohorts are particularly limited by the number of cases that can be unequivocally attributed to asbestos exposure despite other well-known factors (e.g., smoking). Thus, focusing on the genes and chromosomal regions found by these preliminary studies might be useful

and *TRPC3* to be significantly associated with asbestos exposure [83].

and *FOSB*) were down-regulated in asbestos-exposed patients [84].

for more targeted strategies aiming to validate these results.

**3.3 Carcinogenic potential of other fibers**

**78**

cell lines [90].
