Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 116 highlighting the importance of integrating genetic and epigenetic data to advance the field of cancer research and treatment. 2 Genetic Insights in Gastric Cancer 2.1 Oncogenes and tumor suppressor genes Gastric cancer (GC) development is significantly influenced by the interplay between oncogenes and tumor suppressor genes. Oncogenes, when mutated or overexpressed, can drive the proliferation and survival of cancer cells. Conversely, tumor suppressor genes, which normally function to inhibit cell growth and promote apoptosis, can contribute to cancer progression when inactivated. Recent studies have identified several key oncogenes and tumor suppressor genes involved in GC. For instance, the gene PRKAA1, which is part of the PI3K-Alt-mTOR-signaling pathway, has been highlighted as a potential target for drug development due to its significant role in oncogenic processes (Lee et al., 2022). Additionally, the lncRNA lncPSCA has been characterized as a novel tumor suppressor whose expression is regulated by genetic variants associated with GC risk. This lncRNA interacts with DDX5, promoting its degradation and thereby activating p53signaling genes (Zheng et al., 2021). Moreover, the role of epigenetic mechanisms in the regulation of tumor suppressor genes has been increasingly recognized. Promoter methylation is a common mechanism of tumor suppressor gene inactivation in GC, with several genes identified through genome-wide methylation screening showing potential as diagnostic or prognostic biomarkers (Otani et al., 2013). 2.2 Chromosomal aberrations Chromosomal aberrations, including deletions, amplifications, and translocations, are common in GC and contribute to the dysregulation of oncogenes and tumor suppressor genes (Flavahan et al., 2017). These genetic alterations can lead to the loss of tumor suppressor genes or the gain of oncogenes, thereby promoting cancer development and progression. A comprehensive study on the mutational profiling of epigenetic regulation genes in GC revealed significant associations between specific chromosomal aberrations and reduced overall survival in patients. For example, mutations in the genes KMT2D, KMT2C, ARID1A, and CHD7 were found to be mutually exclusive and correlated with poor prognosis, particularly in patients with distant metastases or tumors with signet ring cells (Nemtsova et al., 2021). 2.3 Genome-wide association studies (GWAS) GWAS have been instrumental in identifying genetic variants associated with GC risk. These studies have uncovered numerous single nucleotide polymorphisms (SNPs) and genes that contribute to the genetic predisposition to GC. A systematic review of GWAS on GC identified 226 SNPs located in 91 genes, with 44 genes showing significant associations with GC. Among these, 12 genes were identified as expression quantitative trait loci (eQTL), indicating their potential regulatory roles in GC development. Notably, genes such as PRKAA1, THBS3, and EFNA1 were found to be involved in key signaling pathways like PI3K-Alt-mTOR and p53, highlighting their importance in GC pathogenesis (Figure 1) (Lee et al., 2022). The research of Lee et al. (2022) illustrates the complex biological pathways involved in the mechanisms of gastric cancer, highlighting key proteins and interactions within the PI3K-Akt-mTOR signaling pathway. This pathway is central to cell growth, proliferation, and survival, making it a critical target in cancer research. Genes such as THBS3, EFNA1, and PRKAA1 play pivotal roles in this pathway. THBS3 and EFNA1, through their interactions with integrins and receptor tyrosine kinases (RTKs), initiate downstream signaling that activates PI3K, leading to the phosphorylation and activation of Akt. Akt activation subsequently influences several cellular processes by regulating mTOR, which is involved in protein synthesis, autophagy, and cell survival. MUC1 interacts with other significant proteins like ICAM-1, CD11b, EGFR, Src, and CTNNB1, integrating into the PI3K-Akt-mTOR signaling network and further influencing cancer cell behavior. Additionally, the image shows how external factors such as Helicobacter pylori infection and interactions with eosinophils and other immune components contribute to the inflammatory and pro-apoptotic environment, promoting gastric cancer
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