Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 119 of missense mutations only, portions of samples with missense mutations in KMT2D or KMT2C are colored blue (Adopted from Nemtsova et al., 2021) The research of Nemtsova et al. (2021) provides an analysis of the mutual exclusivity of KMT2D and KMT2C mutations in gastric cancer based on multiple studies. The left panel (a) examines all types of mutations, showing that mutations in KMT2D and KMT2C rarely co-occur within the same sample, as indicated by the combined wPearson p-value of 0.0048. Notably, the TCGA STAD Pan-Cancer study reports the highest mutation rates for KMT2D (17%) and KMT2C (14%). The right panel (b) focuses on missense mutations, demonstrating a similar pattern of mutual exclusivity with a combined wPearson p-value of 0.0082. The Article study shows significant results with 11% of samples having KMT2Dmissense mutations and 6% with KMT2Cmissense mutations. These findings suggest that mutations in KMT2Dand KMT2Care functionally redundant, indicating that either mutation can drive the oncogenic process in gastric cancer, but their co-occurrence is rare. This mutual exclusivity points to distinct but overlapping pathways in cancer development, which could inform targeted therapeutic strategies. Epigenetic alterations, such as DNA methylation and histone modifications, can also affect the expression of genes involved in key cancer-related pathways. For example, the WNT pathway can be activated by mutations in CTNNB1 and by aberrant methylation of its negative regulators, such as DKK3, NKD1, and SFRP1 (Yoda et al., 2015). Similarly, the AKT/mTOR pathway is influenced by mutations in PIK3CA and PTPN11, as well as by epigenetic changes. These interactions underscore the importance of considering both genetic and epigenetic factors in understanding GC. 4.2 Integrated genomic and epigenomic approaches Integrated genomic and epigenomic approaches have provided valuable insights into the molecular mechanisms underlying GC. By combining genetic and epigenetic data, researchers can identify comprehensive profiles of alterations that drive cancer development and progression. For instance, an integrated analysis of cancer-related pathways in GC revealed that genes involved in these pathways are more frequently affected by epigenetic alterations than by genetic mutations (Yoda et al., 2015). This finding suggests that epigenetic changes play a predominant role in the dysregulation of these pathways. Moreover, the use of next-generation sequencing and DNA methylation arrays has enabled the identification of specific epigenetic markers that can serve as potential targets for diagnosis and therapy. For example, aberrant DNA methylation in the promoter regions of tumor suppressor genes is a well-defined hallmark of GC and can be used for early detection and prognosis (Qu et al., 2013; Ebrahimi et al., 2020). Additionally, the inhibition of BET bromodomain proteins, which are epigenetic regulators, has shown promise as a therapeutic approach in GC, particularly in cases with specific genetic and epigenetic alterations (Kang et al., 2017). The interplay between genetic and epigenetic changes in GC is a critical area of research that holds promise for improving our understanding of the disease and developing more effective diagnostic and therapeutic strategies. By integrating genomic and epigenomic data, researchers can uncover the complex mechanisms driving GC and identify novel biomarkers and targets for clinical application. 5 Clinical Implications 5.1 Diagnostic and prognostic biomarkers The identification of reliable biomarkers for gastric cancer (GC) is crucial for early diagnosis and prognosis. Several studies have highlighted the potential of genetic and epigenetic markers in this regard. For instance, a seven-gene signature (FBN1, MMP1, PLAU, SPARC, COL1A2, COL2A1, and ATP4A) has been identified as having significant prognostic value, with high-risk patients showing worse survival outcomes (Wang et al., 2018). Additionally, epigenetic alterations such as DNA methylation and histone modifications are being developed as biomarkers for early detection and prognosis of gastrointestinal cancers (Figure 3), including GC (Wong et al., 2019; Grady et al., 2020). Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have also emerged as promising biomarkers due to their stable expression and regulatory roles in cancer progression (Naeli et al., 2020; Askari et al., 2023).
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