*Oncogenetics of Lung Cancer Induced by Environmental Carcinogens DOI: http://dx.doi.org/10.5772/intechopen.81064*

*Oncogenes and 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.

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

**80**

**4.2 Carcinogenic mechanisms**

*Molecular mechanisms of radon-induced carcinogenesis.*

**Figure 3.**

and conflict with one another [106–108].

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 that are irradiated [111].
