**4.3 Prominent cancer genes affected by radon**

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 mechanism of radon-induced carcinogenesis.

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 pathways between these two environmental agents.

### *Oncogenes and Carcinogenesis*

Taken together, the molecular landscape of radon-induced carcinogenesis is complex and diverse, with effects being observed at the genetic, epigenetic and extracellular level. Future studies may examine the underlying molecular events common to radon-induced lung cancer, to aid in diagnosis and perhaps novel treatment strategies.
