Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 270-278 http://medscipublisher.com/index.php/cge 272 (miRNAs) and long noncoding RNAs (lncRNAs), in the regulation of gene expression through epigenetic mechanisms has been increasingly recognized. These epigenetic changes often interact with genetic mutations, exacerbating the malignant transformation of normal esophageal tissue (Kaz et al., 2016). 4 Gene-Environment Interactions in Esophageal Cancer 4.1 Impact of environmental factors (e.g., smoking, alcohol, diet) on genetic susceptibility Environmental factors such as smoking, alcohol consumption, and diet significantly influence the risk of esophageal cancer through their interactions with genetic predispositions. For example, smoking has been shown to have a strong interaction with genetic polymorphisms in genes like ADH1B and ALDH2, which are involved in alcohol metabolism, increasing the risk of esophageal squamous cell carcinoma (ESCC), particularly in East Asian populations (Suo et al., 2019). Additionally, a study in high-incidence regions of China found that the consumption of alcohol and genetic variants in alcohol dehydrogenase genes significantly amplified the risk of ESCC (Figure 1) (Zhao et al., 2021). Figure 1 The risk stratification of GRS performed on tobacco pack-years, estimated by esophageal squamous cell carcinoma risk (Adopted from Zhao et al., 2021) 4.2 Synergistic effects between genetic predispositions and carcinogenic exposures Synergistic interactions between genetic predispositions and environmental carcinogens, such as tobacco and alcohol, amplify the risk of esophageal cancer. Polymorphisms in genes related to alcohol metabolism, such as ALDH2 and ADH1B, interact with alcohol consumption to substantially increase the risk of ESCC. A study demonstrated that individuals with the ALDH2 rs671 polymorphism and heavy alcohol consumption had a significantly higher risk of ESCC than non-drinkers, illustrating a gene-environment synergy (Mao et al., 2016). Similarly, the interaction between smoking and the PLCE1 gene was identified as a significant factor in increasing esophageal cancer risk (Han et al., 2022). 4.3 Molecular evidence for gene-environment interactions in esophageal cancer Molecular evidence supports the significant role of gene-environment interactions in esophageal cancer. Genes involved in detoxifying carcinogens, such as GSTP1 and CYP2E1, interact with environmental exposures like smoking and alcohol to modulate cancer risk. For example, the CYP2E1 gene, which metabolizes alcohol into
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