Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 120 Figure 3 Schematic diagram showing factors that influence epigenetic alteration formation and the timing of epigenetic alteration formation in GI tract cancer formation (Adopted from Grady et al., 2020) The research of Grady et al. (2020) illustrates the factors influencing the formation of epigenetic alterations in gastrointestinal (GI) tract cancer and their progression over time. Panel A highlights key contributors to epigenetic changes, including aging, lifestyle, diet, and the gut microbiome. These factors interact with an individual's genetic material, leading to modifications that can predispose cells to cancerous transformations. Panel B presents the timeline of cancer development, from normal tissue through benign neoplasia to malignant cancer. It emphasizes the molecular events involved, distinguishing between genetic and epigenetic alterations. Genetic changes accumulate gradually over time, becoming more significant in later stages of cancer progression. In contrast, epigenetic alterations start early and increase steadily, playing a crucial role in the initial stages of tumorigenesis. The diagram underscores the importance of lifestyle and environmental factors in the early stages of cancer development, highlighting potential intervention points for prevention and early detection through lifestyle modifications and monitoring of epigenetic markers. 5.2 Therapeutic targets Epigenetic dysregulation is a hallmark of GC, and targeting these alterations offers new therapeutic opportunities. BET inhibitors, which target bromodomain and extra-terminal domain proteins like BRD4, have shown efficacy in inhibiting GC cell growth by down-regulating oncogenes such as c-Myc (Kang et al., 2017). Furthermore, targeting specific epigenetic mechanisms, such as DNA methylation and histone modifications, has been proposed as a strategy to overcome GC heterogeneity and improve treatment outcomes (Canale et al., 2020). The identification of TGFβ1 and VEGFB as potential therapeutic targets in the tumor microenvironment further underscores the importance of epigenetic regulation in GC therapy (Cai et al., 2020). 5.3 Personalized medicine The heterogeneity of GC necessitates personalized treatment approaches. Genetic and epigenetic profiling can help tailor therapies to individual patients. For example, the GPSGC model, which integrates gene expression data with clinical variables, provides a personalized risk assessment and helps in selecting targeted therapies (Cai et al., 2020). The use of lncRNAs and circRNAs as biomarkers can also guide personalized treatment strategies by identifying specific molecular alterations in each patient (Zhou et al., 2018). Additionally, the development of epigenetic drugs, such as BET inhibitors, offers personalized therapeutic options based on the specific epigenetic landscape of the tumor (Kang et al., 2017). 6 Challenges and Limitations 6.1 Complexity of gastric cancer Gastric cancer (GC) is a highly heterogeneous disease, characterized by a multitude of genetic and epigenetic alterations that complicate its diagnosis and treatment. The intricate interplay between genetic mutations and epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs, contributes to the complexity of GC (Nemtsova et al., 2021; Tang et al., 2022). This heterogeneity is further exacerbated by the
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