Changes in epigenetic information during the occurrence and development of gastric cancer

Abstract

Gastric cancer is one of the most common malignant tumors of the digestive tract, with a high degree of malignancy and poor prognosis. With advancements in disease research, the role of epigenetic changes in its pathogenesis has become a research focus. The known epigenetic changes mainly include DNA methylation, histone modification, and regulation of chromatin structure. This article details the effects of these changes that would result in gastric cancer. Using next-generation sequencing methods and bioinformatics analysis, we can determine the epigenetic changes in abnormal tissues of the digestive tract that facilitate the early diagnosis and treatment of gastric cancer patients. In this article, we summarize how epigenetic changes determine gastric cancer and the new technologies used in research on cancer to benefit gastric cancer patients.

Introduction

Gastric cancer is one of the most common cancers of the digestive tract and the fourth most common cancer worldwide. The number of patients dying from gastric cancer is increasing each year, and the age of gastric cancer patients is becoming increasingly younger (Tian et al., 2022, Ladigan-Badura et al., 2021, Sugimoto et al., 2021). Most gastric cancer patients present with intermediate and advanced stages or have metastases to other parts of the body at the time of diagnosis, resulting in a 5-year survival rate of as low as 1/5 (Sugino et al., 2021, Petrillo et al., 2021). In addition, the early symptoms of gastric cancer lack specificity, and the detection rate of stage I gastric cancer is only 10% (Petryszyn et al., 2020, Xia et al., 2020). Many factors can induce gastric cancer, such as cigarette smoking, alcohol consumption, and a predisposition to gastric cancer (Yaghoobi et al., 2017, Morgagni et al., 2015). Nevertheless, a major cause of gastric cancer is the microorganism Helicobacter pylori, which binds to outer membrane proteins of gastric epithelial cells and uses virulence factors, for example, cytotoxin-associated gene A, to regulate the development of gastric cancer (Liu et al., 2019, Smyth et al., 2020, Alipour, 2021). So far, the mutations in E-cadherin (CDH1), the insulin receptor (PALB2), F-Box Protein 24 (FBXO24), and DOT1-like histone H3K79 methyltransferase (DOT1-L) and the changes in global gene expression between gastric cancer and non-gastric cancer samples have been considered as genetic causes and biomarkers for gastric cancer (Smyth et al., 2020, Wang et al., 2021). Radiation therapy, chemotherapy, and the combination of targeted agents are the main methods currently used to control gastric cancer (Patel and Cecchini, 2020).

Despite current therapy options, people who have advanced gastric cancer have a life expectancy of fewer than 20 months only (Smyth et al., 2020); thus, additional research is required to reverse the situation. Many studies have reported that epigenetic alteration is new evidence and a popular research topic in gastric cancer research (Yeoh and Tan, 2022). Nucleotide and protein modifications are mainly epigenetic forms that drive the global change in gene expression and remodel the structure of nuclear chromatin in cancer cells (Gryder et al., 2022). As a characteristic of epigenetics, covalent histone modification includes methylation, acetylation, small ubiquitination, phosphorylation, and ubiquitination and can be catalyzed by histone modification enzymes. Extensive research on the covalent modification of histones not only aids in the understanding of the related physiological and pathological mechanisms of gene expression and regulation but also provides new insights into the treatment of cancer. This article discusses histone modification and its relationship with tumor occurrence and development, providing new clues for clinical cancer treatment. At present, DNA methylation (Usui et al., 2021) and mismatch repair genes are the most studied phenomena in the molecular mechanisms of gastric cancer pathogenesis (Ebrahimi et al., 2020); relevant studies are at single-gene levels. Normal methylation status can play an important role in cell growth, development, proliferation, differentiation, etc., while abnormal methylation status can cause abnormal cell cycle, DNA damage repair, gene transcription, etc., leading to tumorigenesis. In recent years, the three-dimensional spatial conformation and the function of the genome have gradually become a new focus of genomics research (Yuan et al., 2018, Amjadi-Moheb et al., 2021). Traditional DNA sequencing technologies usually describe the expression of genes as linear. Nevertheless, the arrangement of genetic information is not linear; it is folded and stacked in a three-dimensional configuration to form the three-dimensional structure of chromatin (Wlasnowolski et al., 2020, Akdemir et al., 2020). The enhancer-promoter loop formed by linear DNA folding can promote gene expression. Chromatin structure dysregulation has been demonstrated to drive cancer formation (Gryder et al., 2022).

In the past decade, the rapid development of high-throughput sequencing technology has provided a method for exploring the epigenetic information of chromatin that is not limited to light microscopy. Chromatin Immunoprecipitation (ChIP) is a powerful tool to study protein-DNA interactions in vivo, and is usually used for the study of transcription factor binding sites or histone-specific modification sites. ChIP-Seq technology, which combines ChIP with next-generation sequencing technology, can efficiently detect DNA segments that interact with histones, transcription factors, etc. on a genome-wide scale. Whole-genome bisulfite methylation sequencing (WGBS) can accurately detect the methylation level of all single cytosine bases (C bases) in the whole genome, and is the gold standard for DNA methylation research. WGBS can provide important technical support for the research on the spatiotemporal specific modification of genomic DNA methylation. It can be widely used in the mechanism research of life processes such as ontogeny, aging and disease. It is also the preferred method for the study of methylation profiles of various species. Chromosome conformation capture (3 C) technology and its extensions (4 C, 5 C, Hi-C, and ChIA-PET) enable the analysis of the three-dimensional structure of the nucleus (Sandoval-Velasco et al., 2020, Teng et al., 2015, Jia et al., 2017). In this article, we focused in detail on the mechanisms of DNA methylation and histone modification, which reshape the genome structure and alter the gene expression in cancer cells. We also mentioned several new technologies for studying the relationship between epigenetics, chromatin structure, and cancer, which are crucial for enhancing gastric cancer diagnosis and treatments.