Carcinogenesis
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Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. ⋯ Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients.
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Inflammation can result from a range of sources including microbial infections, exposure to allergens and toxic chemicals, autoimmune disease and obesity. A well-balanced immune response can be anti-tumorigenic; however, a sustained or chronic inflammatory response is generally harmful as the immune response becomes distorted. A causal link between chronic inflammation and cancer is now well accepted and many chronically inflamed organs of the gastrointestinal tract show this association. ⋯ Recently, epigenetic alterations, in particular alterations in DNA methylation, have been observed during inflammation and inflammation-associated carcinogenesis. The mediators of this, the significance of these changes in DNA methylation and the effect this has on gene expression and the malignant transformation of the epithelial cells during IBD and CAC are discussed in this review. The recent advances in technologies to study genome-wide DNA methylation and the therapeutic potential of understanding these molecular mechanisms are also highlighted.
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The observation that mutations in tumor suppressor genes can have haploinsufficient, as well as gain of function and dominant negative, phenotypes has caused a reevaluation of the 'two-hit' model of tumor suppressor inactivation. Here we examine the history of haploinsufficiency and tumor suppressors in order to understand the origin of the 'two-hit' dogma. The two-hit model of tumor suppressor gene inactivation was derived from mathematical modeling of cancer incidence. ⋯ Thus, under certain circumstances, one hit may be sufficient for inactivation. In addition, the phenotypic penetrance of these mutations can vary depending on the nature of the mutation itself, the genetic background, the tissue type, environmental factors and other variables. Incorporating these new findings into existing models of the clonal evolution will be a challenge for the future.
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Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. ⋯ Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.