Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 118 biomarker for early detection and prognosis of gastric cancer has been extensively explored, with promising results (Toiyama et al., 2014). 3.2 Histone modifications Histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination, play a crucial role in the regulation of gene expression by altering chromatin structure and accessibility. In gastric cancer, dysregulation of histone modifications has been implicated in the aberrant expression of genes involved in cancer progression (Dawson and Kouzarides, 2012). For instance, histone deacetylation can lead to the repression of tumor suppressor genes, while histone methylation can either activate or repress gene expression depending on the specific residues modified (Perri et al., 2017). The therapeutic potential of targeting histone modifications has been recognized, with histone deacetylase inhibitors showing promise in preclinical and clinical studies (Jin et al., 2021). These inhibitors can reactivate silenced tumor suppressor genes and inhibit cancer cell growth, offering a novel approach to gastric cancer treatment. 3.3 Non-coding RNAs Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are key regulators of gene expression at the epigenetic level. In gastric cancer, ncRNAs have been shown to play significant roles in tumorigenesis, metastasis, and drug resistance (Toiyama et al., 2014). miRNAs can function as oncogenes or tumor suppressors by targeting mRNAs for degradation or translational repression (Zhou et al., 2017). Dysregulation of miRNAs in gastric cancer can lead to the aberrant expression of genes involved in cell proliferation, apoptosis, and metastasis (Puneet et al., 2018). Similarly, lncRNAs can modulate gene expression through various mechanisms, including chromatin remodeling, transcriptional regulation, and post-transcriptional processing (Zhou et al., 2018). The epigenetic regulation of lncRNAs and their involvement in gastric cancer pathogenesis highlight their potential as therapeutic targets and biomarkers for diagnosis and prognosis. The understanding of epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs in gastric cancer has provided valuable insights into the molecular underpinnings of this malignancy (Calcagno et al., 2013). These epigenetic alterations not only contribute to cancer development and progression but also offer potential avenues for novel therapeutic interventions and biomarker discovery. 4 Interplay Between Genetic and Epigenetic Changes 4.1 Interaction effects The interplay between genetic and epigenetic changes in gastric cancer (GC) is a complex and multifaceted process. Genetic mutations and epigenetic modifications often co-occur and influence each other, contributing to the pathogenesis and progression of GC. For instance, mutations in genes involved in epigenetic regulation, such as KMT2D, KMT2C, ARID1A, and CHD7, have been found to be mutually exclusive (Figure 2), suggesting a potential compensatory mechanism among these genes (Nemtsova et al., 2021). These mutations are significantly associated with reduced overall survival in patients with metastases and tumors with signet ring cells, highlighting their clinical relevance. Figure 2 Analysis of mutual exclusivity of KMT2Dand KMT2Cmutations on the data presented in gastric cancer mutation databases (Adopted from Nemtsova et al., 2021) Image caption: Portions of samples without mutations inKMT2Dor KMT2Care shown in grey; (a) analysis of all types of mutations, excluding amplification and deep deletions, portions of samples with mutations in KMT2Dor KMT2Care colored black; (b) analysis
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