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Cancer Genetics and Epigenetics (online), 2024, Vol. 12, No. 3 ISSN 2369-2995 http://www.medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content A Review of Genetic and Epigenetic Regulation in Gastric Cancer Wei Zhang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 3, 115-124 Prospects of Precision Treatment for Liver Cancer Based on Genome-Wide Association Studies ManmanLi Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 3, 126-136 Personalized and Precise Treatment of Cancer JianWang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 3, 137-143 Integrative Approaches for Predicting Treatment Response in Advanced Solid Tumors Hui Xu Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 3, 144-156 Application of Cancer Mutation Analysis in Drug Development YongCheng Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 2, 157-165
Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 115 Systematic Review Open Access A Review of Genetic and Epigenetic Regulation in Gastric Cancer Wei Zhang Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China Corresponding email: weizhang@qq.com Cancer Genetics and Epigenetics, 2024, Vol.12, No.3 doi: 10.5376/cge.2024.12.0014 Received: 13 Mar., 2024 Accepted: 22 Apr., 2024 Published: 05 May, 2024 Copyright © 2024 Zhang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Zhang W., 2024, A review of genetic and epigenetic regulation in gastric cancer, Cancer Genetics and Epigenetics, 12(3): 115-124 (10.5376/cge.2024.12.0014) Abstract Gastric cancer a leading cause of cancer-related deaths worldwide, necessitating a comprehensive understanding of its underlying mechanisms. This study explores the genetic and epigenetic regulation in gastric cancer, highlighting the critical roles of oncogenes, tumor suppressor genes, and chromosomal aberrations. Genome-wide association studies (GWAS) are discussed for their contributions to identifying genetic predispositions. Additionally, the study delves into epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, and their impact on gene expression. The interplay between genetic and epigenetic changes is examined, emphasizing the interaction effects and the benefits of integrated genomic and epigenomic approaches. Clinical implications are addressed, focusing on diagnostic and prognostic biomarkers, therapeutic targets, and the potential for personalized medicine. The study also considers the challenges and limitations in studying gastric cancer, such as its complexity, technical constraints, and biological variability. Future directions point to the promise of emerging technologies, integrative and multi-omics approaches, and global epidemiological studies in advancing the understanding and treatment of gastric cancer. The study concludes by summarizing key findings and underscoring the importance of ongoing research in this field. Keywords Gastric cancer; Genetic regulation; Epigenetic mechanisms; Biomarkers; Personalized medicine 1 Introduction Gastric cancer (GC) is one of the most prevalent and deadly malignancies worldwide, ranking as the fourth most common cancer and the third leading cause of cancer-related deaths globally (Ebrahimi et al., 2020). The incidence of GC is particularly high in developing countries, where over 70% of new cases and deaths occur (Qu et al., 2013). Despite advancements in diagnosis and treatment, the prognosis for GC remains poor, largely due to late-stage diagnosis and the complex, heterogeneous nature of the disease (Puneet et al., 2018). The pathogenesis of gastric cancer involves a multifaceted interplay between genetic mutations and epigenetic alterations. Genetic mutations, such as those in the TP53, CDH1, and KRAS genes, have long been recognized as critical drivers of GC (Yoda et al., 2015). However, recent research has highlighted the significant role of epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, in the regulation of gene expression and tumor progression (Nemtsova et al., 2021; Capparelli and Iannelli, 2022). Epigenetic changes are heritable yet reversible, making them attractive targets for therapeutic intervention (Puneet et al., 2018; Ebrahimi et al., 2020). For instance, aberrant DNA methylation in the promoter regions of tumor suppressor genes can lead to their inactivation, contributing to oncogenesis (Qu et al., 2013). Similarly, histone modifications and chromatin remodeling can alter the expression of genes involved in cell cycle regulation, apoptosis, and metastasis (Kang et al., 2014; Kang et al., 2017). This study aims to provide a comprehensive overview of the current understanding of genetic and epigenetic regulation in gastric cancer. By synthesizing findings from recent studies, we seek to elucidate the molecular mechanisms underlying GC pathogenesis and progression. The study will cover key genetic mutations and epigenetic alterations, their clinical implications, and potential therapeutic strategies targeting these molecular changes. Through this analysis, we hope to identify gaps in the current knowledge and suggest directions for future research, ultimately contributing to the development of more effective diagnostic and therapeutic approaches for gastric cancer. Understanding the genetic and epigenetic landscape of gastric cancer is crucial for improving patient outcomes. This study will explore the intricate regulatory networks that drive GC,
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
Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 117 progression. Understanding these pathways and interactions is crucial for developing targeted therapies for gastric cancer. Figure 1 Biological pathways of gastric cancer mechanisms (Adopted from Lee et al., 2022) Image caption: THBS3, EFNA1, and PRKAA1 are involved in PI3K-Alt-mTOR-signaling pathway which is the key pathway associated with gastric cancer. MUC1 interacted with ICAM-1, CD11b, EGFR, Src, and CTNNB1 in PPI network is a regulator of the PI3K-Alt-mTOR-signaling pathway. PPI, protein-protein interaction (Adopted from Lee et al., 2022) Furthermore, a meta-analysis of GWAS and prospective cohort studies demonstrated that genetic risk models, such as polygenic risk scores, can effectively stratify individuals based on their risk of developing GC (Tuan et al., 2021). The study of Jin et al. (2020) also emphasized the potential of lifestyle modifications to mitigate the genetic risk of GC, suggesting that individuals with a high genetic risk could substantially reduce their risk by adopting a healthy lifestyle. In summary, the genetic landscape of GC is shaped by a complex interplay of oncogenes, tumor suppressor genes, chromosomal aberrations, and genetic variants identified through GWAS. Understanding these genetic insights is crucial for developing targeted therapies and improving the prognosis of GC patients. 3 Epigenetic Mechanisms in Gastric Cancer 3.1 DNA methylation DNA methylation is a critical epigenetic modification that involves the addition of a methyl group to the cytosine residues in CpG dinucleotides, leading to gene silencing. In gastric cancer, aberrant DNA methylation patterns are frequently observed and are associated with the inactivation of tumor suppressor genes and the activation of oncogenes (Biswas and Rao, 2017). This epigenetic alteration is considered a hallmark of gastric cancer and plays a significant role in its pathogenesis (Ebrahimi et al., 2020). Studies have shown that hypermethylation of promoter regions in tumor suppressor genes can lead to their silencing, contributing to cancer development and progression (Qu et al., 2013). Additionally, global hypomethylation can activate oncogenes, further promoting malignancy (Puneet et al., 2018). The potential of DNA methylation as a
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
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).
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
Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 121 diverse environmental factors and the presence of different molecular subtypes within the same tumor, making it challenging to develop universal therapeutic strategies (Capparelli and Iannelli, 2022). The complexity of GC necessitates a comprehensive understanding of the molecular mechanisms underlying its pathogenesis to identify effective biomarkers and therapeutic targets (Yoda et al., 2015; Khorasani et al., 2021). 6.2 Technical limitations The study of genetic and epigenetic regulation in GC is hindered by several technical limitations. High-throughput sequencing technologies, while powerful, often generate vast amounts of data that require sophisticated bioinformatics tools for analysis and interpretation (Kang et al., 2017). Additionally, the detection of epigenetic modifications, such as DNA methylation and histone modifications, demands highly sensitive and specific assays, which can be technically challenging and costly (Ebrahimi et al., 2020). The variability in sample quality and the need for large, well-characterized cohorts further complicate the identification of consistent and clinically relevant biomarkers (Canale et al., 2020). Moreover, the integration of multi-omics data to provide a holistic view of the genetic and epigenetic landscape of GC remains a significant challenge (Zhou et al., 2018). 6.3 Biological variability Biological variability poses a significant challenge in the study of GC. The genetic and epigenetic landscape of GC can vary widely between patients, and even within different regions of the same tumor (Nemtsova et al., 2021; Capparelli and Iannelli, 2022). This intra-tumor heterogeneity can lead to differential responses to treatment and complicate the identification of universal biomarkers (Canale et al., 2020). Additionally, the dynamic nature of epigenetic modifications, which can be influenced by environmental factors and therapeutic interventions, adds another layer of complexity to the study of GC (Qu et al., 2013). Understanding the biological variability and its implications for disease progression and treatment response is crucial for the development of personalized therapeutic strategies. 7 Future Directions 7.1 Emerging technologies The landscape of gastric cancer research is rapidly evolving with the advent of new technologies that promise to enhance our understanding and treatment of this malignancy. High-throughput sequencing technologies, such as next-generation sequencing (NGS), have revolutionized the field by enabling comprehensive profiling of genetic and epigenetic alterations in gastric cancer (Yoda et al., 2015). These technologies facilitate the identification of novel biomarkers and therapeutic targets, which are crucial for early diagnosis and personalized treatment strategies. Additionally, the development of small molecule inhibitors targeting specific epigenetic regulators, such as BET inhibitors, has shown promising results in preclinical models of gastric cancer (Kang et al., 2017). These inhibitors work by preventing the binding of BET proteins to acetylated histones, thereby inhibiting the transcriptional activation of oncogenes like c-Myc, which are critical for cancer cell survival and proliferation. 7.2 Integrative and multi-omics approaches Integrative and multi-omics approaches are essential for a holistic understanding of gastric cancer. These approaches combine data from genomics, epigenomics, transcriptomics, proteomics, and metabolomics to provide a comprehensive view of the molecular alterations driving gastric cancer. For instance, the interplay between metabolic dysregulations and epigenetic modifications has been shown to contribute significantly to tumor progression (Crispo et al., 2019). By integrating multi-omics data, researchers can identify key regulatory networks and pathways that are disrupted in gastric cancer, leading to the discovery of novel therapeutic targets. Moreover, bioinformatics tools and algorithms are being developed to integrate and analyze these complex datasets, which will enhance our ability to infer the functional roles of specific genetic and epigenetic alterations in cancer (Kagohara et al., 2018). 7.3 Global and epidemiological studies Global and epidemiological studies are crucial for understanding the diverse etiological factors contributing to gastric cancer across different populations. These studies can provide insights into the genetic and epigenetic variations that influence cancer susceptibility and progression in various demographic groups. For example, the
Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 115-124 http://medscipublisher.com/index.php/cge 122 prevalence of specific gene methylation patterns and histone modifications may vary between populations, affecting the efficacy of targeted therapies (Qu et al., 2013). Large-scale epidemiological studies can also identify environmental and lifestyle factors that interact with genetic predispositions to influence gastric cancer risk. By integrating data from global studies, researchers can develop more effective prevention and treatment strategies tailored to specific populations, ultimately improving patient outcomes on a global scale. The future of gastric cancer research lies in the integration of emerging technologies, multi-omics approaches, and global epidemiological studies. These strategies will provide a deeper understanding of the genetic and epigenetic mechanisms underlying gastric cancer, paving the way for innovative therapeutic interventions and personalized medicine. 8 Concluding Remarks The research on genetic and epigenetic regulation in gastric cancer (GC) has revealed significant insights into the mechanisms driving this malignancy. Key findings include the identification of somatic mutations in epigenetic regulation genes such as KMT2D, KMT2C, ARID1A, and CHD7, which are associated with reduced overall survival and metastasis in GC patients. DNA methylation, particularly in promoter regions, has been highlighted as a critical epigenetic modification leading to the inactivation of tumor suppressor genes and the activation of oncogenes, contributing to gastric carcinogenesis. Additionally, the PI3K/Akt/mTOR signaling pathway has been identified as a significant player in GC pathogenesis, with potential for targeted pharmacologic interventions. The role of BET inhibitors in targeting epigenetic regulators like BRD4 has also shown promise as a therapeutic approach. Continued research in the field of genetic and epigenetic regulation in gastric cancer is crucial for several reasons. Firstly, understanding the intricate mechanisms of epigenetic alterations can lead to the identification of novel biomarkers for early diagnosis and prognosis, which is essential given the typically late diagnosis and poor prognosis associated with GC. Secondly, exploring the therapeutic potential of targeting epigenetic modifications, such as DNA methylation and histone modifications, can pave the way for the development of more effective and personalized treatment strategies. Furthermore, investigating the interplay between genetic mutations and epigenetic changes can provide a comprehensive understanding of GC pathogenesis, potentially leading to the discovery of new drug targets and the improvement of existing therapies. In conclusion, the integration of genetic and epigenetic research holds significant promise for advancing our understanding and treatment of gastric cancer. The identification of key epigenetic alterations and their impact on gene expression and tumor behavior underscores the potential of epigenetic therapies in improving patient outcomes. As research progresses, it is imperative to continue exploring the molecular underpinnings of GC and to translate these findings into clinical practice. By doing so, we can move closer to achieving more effective diagnostic tools and therapeutic options, ultimately improving the prognosis and quality of life for patients with gastric cancer. Acknowledgments I extend my sincere thanks to two anonymous peer reviewers for their invaluable feedback on the study. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Askari N., Esfahani B.S., Parvizpour S., Shafieipour S., and Hadizadeh M., 2023, Long non-coding RNAs as potential biomarkers or therapeutic targets in gastric cancer, Gastroenterology and Hepatology from Bed to Bench, 16(3): 297. Biswas S., and Rao C.M., 2017, Epigenetics in cancer: fundamentals and beyond, Pharmacology and Therapeutics, 173: 118-134. https://doi.org/10.1016/j.pharmthera.2017.02.011 Cai W.Y., Dong Z.N., Fu X.T., Lin L.Y., Wang L., Ye G.D., Luo Q., and Chen Y.C., 2020, Identification of a tumor microenvironment-relevant gene set-based prognostic signature and related therapy targets in gastric cancer, Theranostics, 10(19): 8633. https://doi.org/10.7150/thno.47938
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Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 125-136 http://medscipublisher.com/index.php/cge 125 Review Article Open Access Prospects of Precision Treatment for Liver Cancer Based on Genome-Wide Association Studies ManmanLi Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding email: manman.li@hibio.com Cancer Genetics and Epigenetics, 2024, Vol.12, No.3 doi: 10.5376/cge.2024.12.0015 Received: 26 Mar., 2024 Accepted: 05 May, 2024 Published: 18 May, 2024 Copyright © 2024 Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li M.M., 2024, Prospects of precision treatment for liver cancer based on genome-wide association studies, Cancer Genetics and Epigenetics, 12(3): 126-136 (doi: 10.5376/cge.2024.12.0015) Abstract Liver cancer remains a significant global health challenge, necessitating advanced treatment strategies such as precision medicine. This study explores the potential of genome-wide association studies (GWAS) to enhance precision treatment for liver cancer. It provides a comprehensive study of the progress in liver cancer research, highlighting advancements in molecular profiling, identification of molecular subtypes, and genomic alterations. It delves into the genetic insights gained from GWAS, including significant genetic variants and epigenetic factors. The study also discusses how to integrate GWAS findings into clinical practice, emphasizing translational research, personalized treatment plans, and clinical implementation. Case studies and clinical trials are presented to showcase successful implementations, ongoing trials, and lessons learned. Current challenges in precision treatment, such as tumor heterogeneity, drug resistance, and data interpretation, are examined. Additionally, the study studys advances in technology and methodology, including next-generation sequencing (NGS), CRISPR and genome editing, and bioinformatics. Future perspectives, including emerging therapies, the role of artificial intelligence, and the importance of collaborative research, are discussed. This study underscores the transformative potential of GWAS in liver cancer treatment and highlights the need for continued research and technological innovation. Keywords Liver cancer; Precision medicine; Genome-wide association studies (GWAS); Personalized treatment; Genetic variants 1 Introduction Liver cancer is a significant global health concern, ranking as the third leading cause of cancer-related deaths worldwide (Nakagawa et al., 2019). The disease is characterized by its high heterogeneity and poor prognosis, with various etiological factors such as hepatitis B and C infections, aflatoxin exposure, alcohol consumption, and metabolic diseases contributing to its development (Yi and Sahni, 2017). Despite advances in understanding the molecular mechanisms underlying liver cancer, early diagnosis remains challenging, and the survival rate is notably low due to rapid disease progression and limited effective treatment options. Precision medicine represents a paradigm shift in cancer treatment, moving away from one-size-fits-all approaches to more personalized strategies that consider individual genetic, environmental, and lifestyle factors (Zugazagoitia et al., 2016). This approach has shown promise in improving treatment outcomes by targeting specific molecular alterations within tumors. Precision oncology, a subset of precision medicine, involves the use of genomic and molecular profiling to guide the selection of targeted therapies and immunotherapies, thereby optimizing treatment efficacy and minimizing adverse effects (Sicklick et al., 2019). However, challenges such as tumor heterogeneity, acquired resistance, and the complexity of interpreting large genomic datasets remain significant hurdles. Genome-Wide Association Studies (GWAS) have emerged as a powerful tool in identifying genetic variants associated with various diseases, including liver cancer. By analyzing the genomes of large populations, GWAS can uncover common genetic markers that contribute to disease susceptibility and progression (Tsimberidou et al., 2020). In liver cancer, GWAS have identified several driver genes and mutations, such as those involved in the Wnt/β-catenin pathway, TP53/cell-cycle pathways, and telomere maintenance, which are crucial for hepatocarcinogenesis. These findings provide valuable insights into the molecular underpinnings of liver cancer and offer potential targets for precision treatment (Qiu et al., 2019).
Cancer Genetics and Epigenetics 2024, Vol.12, No.3, 125-136 http://medscipublisher.com/index.php/cge 126 The study is to explore the prospects of precision treatment for liver cancer based on findings from Genome-Wide Association Studies. By synthesizing current research, highlight the potential of GWAS in identifying actionable genetic alterations and guiding personalized therapeutic strategies. The ultimate goal is to improve clinical outcomes for liver cancer patients through the integration of genomic data into precision medicine frameworks. 2 Progress in Liver Cancer Research 2.1 Advancements in molecular profiling Recent advancements in molecular profiling have significantly enhanced our understanding of liver cancer and its treatment. The integration of genomic and transcriptomic profiling has been pivotal in expanding precision cancer medicine. For instance, the WINTHER trial demonstrated that both DNA and RNA profiling could improve therapy recommendations and patient outcomes by identifying actionable mutations and guiding personalized treatment strategies (Rodón et al., 2019). Similarly, the MSK-IMPACT initiative has provided comprehensive genomic data from over 10,000 patients, revealing clinically relevant somatic mutations and novel noncoding alterations that can be targeted therapeutically. These large-scale profiling efforts underscore the importance of extensive molecular characterization in developing effective precision treatments for liver cancer. 2.2 Identification of molecular subtypes The identification of molecular subtypes in liver cancer has been a crucial step towards personalized medicine. Genome sequencing studies have classified liver cancer into distinct molecular subtypes based on somatic mutation profiles, RNA expression profiles, and DNA methylation profiles, which are associated with patient prognosis (Nakagawa et al., 2019). This classification enables the stratification of patients into subgroups that may respond differently to specific therapies. For example, the I-PREDICT study highlighted the feasibility of using tumor DNA sequencing to recommend individualized combination therapies, which improved disease control rates and survival outcomes (Sicklick et al., 2019). These findings illustrate the potential of molecular subtyping to tailor treatments to the unique genetic makeup of each patient's tumor. 2.3 Genomic alterations in liver cancer Genomic alterations play a critical role in the pathogenesis and progression of liver cancer. Comprehensive genomic studies have identified key driver mutations and pathways involved in hepatocarcinogenesis, such as the Wnt/β-catenin pathway, TP53/cell-cycle pathways, and telomere maintenance mechanisms. Additionally, structural variants, copy-number alterations, and virus integrations, particularly HBV integration into cancer-related genes, have been recognized as significant contributors to liver cancer development. The PERMED-01 clinical trial further demonstrated that extensive molecular profiling could identify actionable genetic alterations in a majority of patients, leading to matched therapies that improve clinical outcomes (Bertucci et al., 2019). These insights into the genomic landscape of liver cancer are essential for developing targeted therapies and improving patient prognosis. In summary, the progress in liver cancer research, driven by advancements in molecular profiling, the identification of molecular subtypes, and the understanding of genomic alterations, holds great promise for the future of precision treatment in liver cancer. By leveraging these insights, researchers and clinicians can develop more effective, personalized treatment strategies that improve patient outcomes (Malone et al., 2020). 3 Genetic Insights from GWAS in Liver Cancer 3.1 Methodology of GWAS Genome-wide association studies (GWAS) have become a cornerstone in understanding the genetic underpinnings of various diseases, including liver cancer. The methodology involves scanning the entire genome of numerous individuals to identify genetic variants associated with specific traits or diseases. This approach has been instrumental in identifying biomarkers and genetic risk factors that contribute to liver cancer susceptibility and progression (Masotti et al., 2019). Typically, GWAS involves the collection of DNA samples from both affected individuals (cases) and unaffected individuals (controls). These samples are then genotyped to detect single nucleotide polymorphisms (SNPs) and other genetic variations. Advanced statistical methods are employed to analyze the data, aiming to find significant associations between genetic variants and liver cancer (Yadav et al., 2021).
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