**4.1 Physiological and molecular impact of exposure**

Radon is the second most common cause of lung cancer in many countries; however, the intricacies of its mechanism of action remain underappreciated. The genotoxicity of radon is largely the result of alpha particle emission during its spontaneous decay into short-lived radioactive progeny (218Po and 214Po) and comparably long-lived radioactive 210Pb, which also induces cellular damage through alpha decay (**Figure 3**) [98].

Alpha decay is the emission of a 4 atomic mass unit helium ion (two protons and two neutrons), which can liberate electrons from water molecules and result in the generation of several types of ROS [15]. Much like the mechanisms of arsenic and asbestos toxicity, ROS generated as a consequence of radon exposure can lead to widespread molecular aberrations, especially base oxidation (leading to mismatches and mutagenesis), DNA strand breaks, chromosomal aberrations, and deletions. For example, chromatid deletions in blood lymphocytes may be a result of radon exposure, which may in part explain the associations between radon exposure and blood malignancies [8]. These events may occur at levels well below those currently deemed safe in many countries, exemplified by the observation of chromosomal abnormalities in lymphocytes at very low doses of polonium-214, a radioactive progeny of radon [99].

Beyond the molecular events resulting from ROS generation, alpha radiation from radon exposure can induce bystander responses in cells that have not been directly affected by alpha particles [100]. The bystander effect of radiation exposure can occur through the release of signals from nearby irradiated cells, generating a physiological response in non-irradiated cells, even at relatively low doses of radiation [101]. The effect requires direct contact between adjacent cells, such as through gap junctions, as well as compounds in the surrounding medium, including cytokines [102]. One of these compounds, nitric oxide (NO), has been shown to be an important factor for the cell-killing effects of the bystander response, largely through the direct interaction with and damage of DNA [103]. Moreover, NO byproducts such as dinitrogen trioxide (N2O3) can promote nitrosation of other amines, such as those of DNA bases, leading to cross-linking and DNA alkylation [102]. Another compound that may be relevant to the bystander effect of cellular

## **Figure 3.**

*Molecular mechanisms of radon-induced carcinogenesis.*

radiation exposure is cyclooxygenase 2 (COX-2), which is related to the NF-κB pathway, an effect that is attenuated upon COX-2 inhibition [103, 104]. Finally, this response may be dependent on *TP53* status, which will be discussed in Section 4.3.

## **4.2 Carcinogenic mechanisms**

Despite differences in the details of exposure, the molecular mechanisms contributing to carcinogenesis in individuals exposed to arsenic, asbestos, and radon converge in that they all produce ROS. Radon has a half-life of 3.8 days, and as previously mentioned, commonly generates alpha particles and polonium decay products, which themselves emit further alpha radiation [105]. Alpha particles have a high linear energy transfer (LET) despite having relatively low penetration capability, meaning that they interact readily with DNA, especially in regions close to their site of exposure, such as the bronchial epithelium [105]. Thus, it is not surprising that lung malignancies are the most common type of radon-induced cancer. High LET radiation is distinct from low LET radiation (such as x-rays or gamma rays) in that it produces a substantially greater proportion of clustered damage, meaning the occurrence of ≥2 lesions of ≥1 different types within 1–2 helical turns of DNA. Clustered DNA damage is typically repaired with slower kinetics and has a greater likelihood of producing sequence alterations, as repair pathways converge and conflict with one another [106–108].

**81**

*Oncogenetics of Lung Cancer Induced by Environmental Carcinogens*

The largest radon-induced mechanisms of carcinogenesis include DNA damage, ROS, and alpha particle generation; likewise, pathways associated with these functions are also known to be associated with lung cancer. In fact, patients positive for rearrangements in the gene encoding anaplastic lymphoma kinase (*ALK*)—an event frequently found to drive lung tumorigenesis—were found to have two-fold increases in residential radon levels than those without these rearrangements [109, 110]. While a synergistic effect between radon and smoking has been suggested [11], the G:C to T:A transversions associated with tobacco-related molecular damage are not as commonly observed in individuals exposed to radon, suggesting a unique molecular signature in radon-associated lung tumors [15]. Again, it is important to note that a number of the pathways affected by radon exposure, including gene expression alterations and apoptotic disturbances, may actually be from cells neighboring those that are irradiated [104]. In fact, pro-inflammatory and ROS-generating cytokines such as tumor necrosis factor alpha (TNF-α) may be released upon radiation exposure, which may perpetuate the damage enacted by ROS [111]. Thus, key pathways such as DNA repair, proliferation, and cell death can be altered in cells beyond those

ROS-induced DNA damage is a large factor in radon-induced carcinogenesis, thus, many of the examinations into genes affected by radon are relevant to DNArepair and apoptotic pathways. Naturally, a heavy focus is placed on *TP53.* Many investigations into *TP53* examine whether hotspot mutations in *TP53* can act as a molecular signal for radon-induced genotoxicity in at-risk populations. Although *TP53* is observed to be altered in high exposure populations, there are limited observations available to suggest a consistent mutational landscape [112]. However, the role of *TP53* in the molecular response to radon exposure may be relevant to the bystander effect, wherein *TP53* may mediate the inhibition of response signals coming from irradiated cells [103]. Additionally, other key lung cancer-related genes may also be mutated by radon exposure, including *EGFR* and phosphatase and tensin homolog (*PTEN*), but the exact mechanisms remain to be characterized [113]. As previously discussed, radon may also exhibit its carcinogenic effects epigenetically, as evidenced by the promoter hypermethylation of the tumor suppressor genes *CDKN2A* and *MGMT.* In normal human lung cell lines, miRNAs shown to be primarily involved in cell proliferation, differentiation, and adhesion displayed aberrant expression upon radon exposure [114]. Moreover, the miRNA *let-7e*—an epigenetic regulator of the RAS oncogene—was found to be upregulated upon low radon exposure [115]. In this study, the upregulation of miRNAs targeting tumor suppressor genes was also noted, including *PTEN*, which may present an alternative

Finally, a number of studies have examined the effect of genetic polymorphisms of DNA damage repair genes in the outcome of individuals exposed to radon. For instance, individuals with a polymorphism leading to the Asp1104His substitution of DNA repair gene *ERCC5* (XpG) displayed a higher frequency of micronuclei in their lymphocytes, representative of elevated cytogenetic damage and decreased radiosensitivity [116]. Alternatively, the absence of *GSTM1* and *GSTT1*, members of the glutathione-s-transferase enzyme family—critical to detoxification and excretion is associated with an increased risk of lung cancer development [117, 118]. When radon exposure is considered, individuals with null alleles show a doubly increased odds ratio of lung cancer development [118]. Notably, this enzyme is relevant in the biotransformation and excretion of arsenic, suggesting similar carcinogenic path-

*DOI: http://dx.doi.org/10.5772/intechopen.81064*

that are irradiated [111].

**4.3 Prominent cancer genes affected by radon**

mechanism of radon-induced carcinogenesis.

ways between these two environmental agents.
