**5. Common oncogenic features exhibited by environmental carcinogens**

The landscape of the genomic disruptions induced by environmental carcinogens is extensive. It has been demonstrated that these compounds can induce alterations such as chromosomal abnormalities, DNA double-strand breaks, gene expression dysregulation, and epigenetic aberrations. While each agent presents a unique mechanism and clinical challenge, a number of parallels can be seen. The molecular effects of exposure to arsenic, asbestos, and radon converge in that each compound can result in DNA damage induced by ROS and inflammation. As these events occur early during tumor development, the identification of the underlying genomic and epigenomic abnormalities caused by these compounds is extremely relevant in identifying early oncogenic events and individual susceptibility differences.

Although the intricacies of the molecular mechanisms of alteration may differ between the various toxic agents, ROS generation is a common outcome of exposure that can lead to extensive DNA damage and further perturbations in various cellular compartments and processes [119]. As mitochondria are one of the primary sources of ROS, they are also key targets of oxidative toxicity [120]. Arsenic exposure is associated with dysfunction of the mitochondria, through the ability of its metabolites to disrupt the mitochondrial membrane potential and reduce mitochondrial ATP levels, as well as ROS-induced mitochondrial damage [121, 122]. Mitochondrial damage induced by arsenic can then lead to numerous alterations in key signaling pathways, such as the decreased expression of apoptotic regulator protein Bcl-2 [122]. Regardless of the molecular mechanism, mitochondrial insult culminates in apoptosis and increased inflammation, in addition to the exacerbation of reactive species generation; events that commonly precede tumorigenesis [121, 123].

Another frequently observed early consequence of exposure to environmental carcinogens is an inflammatory response. Indeed, inflammation caused by infiltrating immune cells underlies numerous hallmarks of cancer biology by providing key molecules for tumor survival and growth, as well as the promotion of genomic aberrations, again through the generation of ROS [124]. Asbestos-induced carcinogenesis is thought to rely heavily on the inflammatory response, where the macrophages of the innate immune system attempt to clear the carcinogenic fibers through phagocytosis [125]. However, these fibers are inherently difficult to digest, leading to the eventual death of the macrophage and subsequent release of proinflammatory cytokines, ROS, and other growth factors [126]. Interestingly, many malignancies have noticeable local immune responses prior to tumor development, highlighting the complex and dichotomous role of host immune cells in both proand anti-tumor functions [127]. Thus, exposure to environmental carcinogens threatens the genetic and epigenetic landscape of oncogene expression in the development of malignancies, and subsequently changes cellular and systemic processes.

The intertwined role of genetic and epigenetic aberrations resulting from exposure to these compounds highlights the complexity of environmentally-induced lung cancer. However, the carcinogenic mechanisms associated with exposure to these agents have been mainly identified using a "one-agent-at-a-time" approach. Further, we have yet to understand how these factors interplay with one another in cases of

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*Oncogenetics of Lung Cancer Induced by Environmental Carcinogens*

combined exposure and how individual genomes modulate the molecular events that arise following exposure. For example, it is difficult to accurately assess the relative risk of lung cancer in an individual who is exposed to occupational asbestos, arsenic-contaminated water, and high levels of domestic indoor air radon. Whether these factors synergize in terms of their molecular effects is not clearly understood and has critical implications to patient monitoring and disease management.

Recently, the idea of the human exposome has sought to provide a method for analyzing individual risk factors by integrating the effects of factors ranging from DNA-level alterations to geographic location. The human exposome is defined as the sum of every exposure to which an individual is subjected to from conception to death [128]. The exposome is dynamic: the nature, amount, and conditions of exposure change over time. It also includes exposure from internal (e.g., metabolism, endogenous hormones, gut microflora, inflammation, oxidative stress, etc.) and external (e.g., radiation, infectious agents, chemical contaminants and environmental pollutants, among others) sources [129]. The lungs are one of the organs at the highest risk of disease development from environmental exposures as the lung exposome can be comprised of an array of molecules and environmental insults. Arsenic, asbestos, and radon, together with air pollution and tobacco smoke, constitute a fraction of the complex mix of environmental carcinogens posing risks for developing thoracic malignancies in humans. However, understanding the oncogenic events following exposure to these agents may allow for the identification of key intervention points to minimize environmentally-induced lung cancer in

**6. Translational outlook for environmentally-induced cancer**

As the molecular mechanisms of environmentally-induced carcinogenesis continue to emerge, a need to characterize the clinical utility of these findings should be underscored. This need is further emphasized by the complex interplay between the numerous features of the lung exposome. Many of the single cancer-associated genes that are affected by exposure to these environmental agents are promising therapeutic intervention points. For instance, targeted inhibitors of EGFR (e.g., erlotinib, afatinib)—a protein transcribed from a gene commonly up-regulated upon exposure to arsenic—are used in lung cancer treatment to interfere with the aberrant growth pathways activated by the upregulation of this signaling receptor [130]. Additionally, the association between radon exposure and *ALK* gene rearrangements in lung cancer patients may be amenable to therapy with inhibitors of the ALK protein (e.g., crizotinib, ceritinib) [131]. However, patients that do not present with alterations in genes that are clinically actionable remain extremely difficult to treat beyond standard regimes. Thus, it is critical to analyze the oncogenetic alterations induced by environmental carcinogens, to not only identify the contribution of each of these widely-distributed agents to tumorigenesis, but also to direct the development of novel treatment and risk-management strategies. Concurrent analysis of altered genes, transcripts, and proteins may help to parse out the risk associated with the varying molecular aberrations that have been observed to be induced by these compounds [132]. This approach, while difficult in terms of scale, necessitates the use of geographic, demographic, and exposome level data, which can be scarce in areas where environmental carcinogen levels are especially concerning. **Table 1** summarizes the currently available sources of information for carcinogens found in the environment that are associated with lung cancer. Overall, future mitigation of the environmental risk factors that lead to lung cancer will rely on the integration of information from the genomic to epidemiological levels.

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

at-risk populations.
