Subtypes Of Gastric Cancer Research Articles

Integrated Analysis of Serum and Tissue microRNA Transcriptome for Biomarker Discovery in Gastric Cancer.

Gastric cancer (GC) poses a significant global health challenge, demanding a detailed exploration of its molecular landscape. Studies suggest that exposure to environmental pollutants can lead to changes in microRNA (miRNA) expression patterns, which may contribute to the development and progression of GC. MiRNAs have emerged as crucial regulators implicated in GC pathogenesis. The largest GC serum miRNA dataset to date, comprising 1417 non-cancer controls and 1417 GC samples was used. We conducted a comprehensive analysis of miRNA expression profiles. Differential expression analysis, co-expression network construction, and machine learning models were employed to identify key serum miRNAs and their association with clinical parameters. Weighted Gene Co-expression Network Analysis (WGCNA) and immune infiltration analysis were used to validate the importance of the key miRNA. A total of 1766 differentially expressed miRNAs were identified, with miR-1290, miR-1246, and miR-451a among the top up-regulated, and miR-6875-5p, miR-6784-5p, miR-1228-5p, and miR-6765-5p among the top down-regulated. WGCNA revealed that modules M1 and M5 were significantly associated with GC subtypes and disease status. MiRNA-target gene network analysis identified prognostically significant genes TP53, EMCN, CBX8, and ALDH1A3. Machine learning models LASSO, SVM, randomforest, and XGBOOST demonstrated the diagnostic potential of miRNA profiles. Tissue and serum miR-187 emerged as an independent prognostic factor, influencing patient survival across clinical parameters. Gene expression and immune cell infiltration were different in tissues stratified by miR-187 expression. In summary, the integration of differential gene expression, co-expression analysis, and immune cell profiling provided insights into the molecular intricacies of GC progression.

Host repair polymorphisms and H. pylori genes in gastric disease outcomes: Who are the guardian and villains?

Gastric cancer (GC) is the fourth-leading cause of cancer-related mortality. The intestinal subtype of GC comes after the cascade of Correa, presenting H. pylori infection as the major etiological factor. One of the main mechanisms proposed for the progression from a more benign gastric lesion to cancer is DNA damage caused by chronic inflammation. Polymorphisms in DNA repair genes can lead to an imbalance of host DNA damage and repair, contributing to the development of GC. From there, we evaluated the risk of polymorphisms in DNA repair system genes in progressive gastric diseases and their association with the H. pylori genotype. This study included 504 patients from two public hospitals in Brazil’s north and northeast regions. The samples were classified into active and inactive gastritis, metaplasia, and GC. Polymorphisms in the DNA repair genes MLH1-93G > A, APE1 2197 T > G, XRCC1 28,152 G > A, MGMT 533 A > G, and XRCC3 18,067C > T were investigated by RFLP-PCR and H. pylori genotype by PCR. Statistical analyses were conducted using EPINFO 7.0., SNPSTAT, and CART software. The XRCC1 (GA) polymorphic allele stood out because it was associated with a lower risk of more severe gastric disease progression. Haplotypes of XRCC1 (GA) associated with some genotypes of MGMT, XRCC3, MLH1, and APE1 also showed protection against the progression of gastric diseases. XRCC3 (CT) showed a decreased risk of gastric disease progression in women, while a risk 1.3x to GC was observed in the MLH1 (A) polymorphic allele. The interaction between H. pylori genes and the host showed that the H. pylori cagE gene was the most important virulence factor associated with a worse clinical outcome, even overlapping with the XRCC1 polymorphism, where the MLH1 polymorphism response varied according to vacA alleles. Our results show the relevance of XRCC1 G > A for genome integrity, sex influence, and interaction between H. pylori virulence factors and XRCC1 and MLH1 genotypes for gastric lesion outcomes in Brazilian populations.

Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹ untranslated region (3ʹUTR) of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer.

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3' untranslated region (3'UTR) of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

Integrated analysis to identify biological features and molecular markers of poorly cohesive gastric carcinoma (PCC)

As one of the two main histologic subtypes of gastric cancer (GC), diffuse-type gastric cancer (DGC) containing poorly cohesive gastric carcinoma (PCC) components has a worse prognosis and does not respond well to typical therapies. Despite the large number of studies revealing the complex pathogenic network of DGC, the molecular heterogeneity of DGC is still not fully understood. We obtained single-cell RNA-seq data and bulk data from the tumor immune single cell hub, the public gene expression omnibus, and the cancer genome atlas databases. A series of bioinformatics analyses were performed using R software. Immunofluorescence staining, hematoxylin and eosin staining, western blot, and functional experiments were used for experimental validation. Caudin-3, -4 and -7 were lowly expressed in DGC and their expression levels were further reduced in PCC. The PCC components were mainly located in the deeper layers of the DGC and had a high level of hypoxic Wnt/β-catenin signaling and stemness. We further identified Insulin Like Growth Factor Binding Protein 7 (IGFBP7) as a marker for PCC components in the deep layer. IGFBP7 is stimulated by hypoxia and promotes cancer cell invasiveness and reduced claudin expression. In addition, programmed death-1 ligand (PD-L1) was specifically expressed in the deep layer, reflecting deep layer-specific immunosuppression. The PCC components are predominantly situated in the deeper layers of DGC. Initial molecular characterization of these PCC components revealed distinct features, including low expression of claudin-3, -4, and -7, high expression of IGFBP7, and the presence of PD-L1. These molecular traits may partially account for the pronounced tumor heterogeneity observed in GC.

Expression of claudin 18.2 in poorly cohesive carcinoma and its association with clinicopathologic parameters in East Asian patients

BackgroundPoorly cohesive carcinoma (PCC) is a distinct subtype of gastric cancer with limited therapeutic options. This study investigated claudin (CLDN) 18.2 expression status in PCCs using a 43–13 A clone. MethodsWe retrospectively collected 178 consecutive surgically resected stage Ⅱ–Ⅲ gastric cancer samples. Tissue microarray blocks were constructed for CLDN18.2 immunohistochemical staining. We studied CLDN18.2 expression and its association with clinicopathologic parameters. ResultsCLDN18.2 positivity (defined by ≥ 75 % of tumor cells showing moderate to strong membranous positivity) was found in 34.8 % of the PCC cases (62/178). Approximately half of the CLDN18.2 positive PCCs demonstrated heterogeneous expression (51.6 %, 32/62). CLDN18.2 positivity was not associated with any clinicopathologic parameters examined. However, CLDN18.2 positivity tended to be more frequent in E-cadherin-positive PCCs (no loss of expression) than in E-cadherin-negative PCCs (loss of expression) (50 % vs. 27.7 %). The CLDN18.2 expression level, represented by the H-score, gradually decreased as the paraffin block storage time increased (P = 0.046). Overall survival and disease-free survival analyses showed no significant difference between CLDN18.2-positive and negative PCCs. ConclusionsA significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.

Preclinical evaluation of fenretinide against primary and metastatic intestinal type‑gastric cancer.

In recent years there has been a decline in the incidence of gastric cancer, however the high mortality rate has remained constant. The present study evaluated the potential effects of the retinoid fenretinide on the viability and migration of two cell lines, AGS and NCI-N87, that represented primary and metastatic intestinal gastric cancer subtypes, respectively. It was determined that a similar2 dose of fenretinide reduced the viability of both the primary and metastatic cell lines. In addition, it was demonstrated that combined treatment with fenretinide and cisplatin may affect the viability of both primary and metastatic gastric cancer cells. Furthermore, a wound healing assay demonstrated an inhibitory effect for fenretinide on cell migration. As part of the characterization of the mechanism of action, the effect of fenretinide on reactive oxygen species production and lipid droplet content was evaluated, with the latter as an indirect means of assessing autophagy. These results support the hypothesis of combining using fenretinide with conventional therapies to improve survival rates in advanced or metastatic gastric cancer.

Development of a staging system for hepatoid adenocarcinoma of the stomach based on multicenter data: A retrospective cohort study: A Staging System for Hepatoid Adenocarcinoma of the Stomach.

Hepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer (GC) with a poor prognosis. Furthermore, the current pathological staging system for HAS does not distinguish it from that for common gastric cancer (CGC). The clinicopathological data of 251 patients with primary HAS who underwent radical surgery at 14 centers in China from April 2004 to December 2019 and 5082 patients with primary CGC who underwent radical surgery at 2 centers during the same period were retrospectively analyzed. A modified staging system was established based on the differences in survival. After 1:4 propensity score matching (PSM), 228 patients with HAS and 828 patients with CGC were analyzed. Kaplan-Meier (K-M) analysis showed patients with HAS had a poorer prognosis compared with CGC. Multivariate analysis identified pN stage, CEA level, and perineural invasion (PNI) as independent prognostic factors in patients with HAS. A modified pT (mpT) staging was derived using recursive partitioning analysis (RPA) incorporating PNI and pT staging. The modified pathological staging system (mpTNM) integrated the mpT and the 8th American Joint Committee on Cancer (AJCC) pN definitions. Multivariate analysis showed that mpTNM stage outperformed other pathological variables as independent predictors of OS and RFS in patients with HAS. The mpTNM staging system exhibited significantly higher predictive accuracy for 3-year OS in patients with HAS (0.707, 95% CI: 0.650-0.763) compared to that of the 8th AJCC staging system (0.667, 95% CI: 0.610-0.723, P<0.05). Analysis using the Akaike information criterion favored the mpTNM staging system over the 8th AJCC staging system (824.69 vs. 835.94) regarding the goodness of fit. The mpTNM stages showed improved homogeneity in survival prediction (likelihood ratio: 41.51 vs. 27.10). Comparatively the mpTNM staging system outperformed the 8th AJCC staging system in survival prediction, supported by improvements in the net reclassification index (NRI: 47.7%) and integrated discrimination improvement (IDI: 0.083, P<0.05). Time-dependent ROC curve showed that the mpTNM staging system consistently outperformed the 8th AJCC staging system with increasing observation time. The mpTNM staging system exhibited superior postoperative prognostic accuracy for patients with HAS compared to the 8th AJCC staging system.

Single-cell RNA Sequencing Demonstrates the Heterogeneity of Different Molecular Subtypes in Gastric Cancer

Single-cell RNA Sequencing Demonstrates the Heterogeneity of Different Molecular Subtypes in Gastric Cancer

Clinicopathological Characteristics and Lymph Node Metastasis Rates in Early Gastric Lymphoepithelioma-Like Carcinoma: Implications for Endoscopic Resection.

Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric cancer. We aimed to identify the clinicopathological features and rate of lymph node metastasis (LNM) to investigate the feasibility of endoscopic submucosal dissection for early gastric LELC confined to the mucosa or submucosa. We compared the clinicopathological characteristics of 116 early gastric LELC patients and 5,753 early gastric well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients treated by gastrectomy. Compared to WD or MD early gastric cancer (EGC) patients, early LELC patients were younger and had a higher prevalence of proximally located tumors. Despite more frequent deep submucosal invasion (86.2% vs 29.8%), lymphatic invasion was less frequent (6.0% vs 16.2%) in early LELC patients than in WD or MD EGC patients. Among tumors with deep submucosal invasion, the tumor size was smaller, lymphatic invasion was less frequent (6.0% vs 40.2%) and the rate of LNM was lower (10.0% vs 19.4%) in patients with LELC than in those with WD or MD EGC. The overall rate of LNM in early LELC patients was 8.6% (10/116). The risk of LNM in patients with mucosal, shallow submucosal invasive, or deep submucosal invasive LELC was 0% (0/6), 0% (0/10), and 10% (10/100), respectively. Early LELC is a distinct subtype of EGC with more frequent deep submucosal invasion but less lymphatic invasion and LNM than WD or MD EGCs. Endoscopic submucosal dissection may be considered curative for patients with early LELC confined to the mucosa or shallow submucosa, given its negligible rate of LNM.

High levels of tumor cell-intrinsic STING signaling are associated with increased infiltration of CD8+ T cells in dMMR/MSI-H gastric cancer

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (−)] GC. The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS–STING was highly expressed in dMMR GC compared to pMMR/EBV (−) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8+ tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (−). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment.

Developing a prognostic signature: identifying differentially expressed genes in cardia and non-cardia gastric cancer for immunity and therapeutic sensitivity analysis.

Gastric cancer (GC) can be anatomically categorized into two subtypes; that is, cardia gastric cancer (CGC) and non-cardia gastric cancer (NCGC), which have distinct molecular mechanisms and prognoses. At present, the majority of pharmacological interventions for GC adhere to non-specific treatment regimens. The stratification of GC based on molecular disparities between CGC and NCGC has important clinical guidance value and could help in the development of precision therapies tailored to individual patient needs. Nevertheless, research in this specialized field remains notably limited. This study aims to investigate the molecular differences between CGC and NCGC and to leverage these differences to develop a prognostic risk scoring model (PRSM). We used patient data from The Cancer Genome Atlas (TCGA) and performed a differentially expressed gene (DEG) analysis between CGC and NCGC. A PRSM was developed from the prognosis-associated DEGs identified through Cox regression analyses and was well validated using Gene Expression Omnibus (GEO) data. A total of 339 DEGs were identified between CGC and NCGC, and four prognosis-associated genes were used to construct the PRSM. Using the risk coefficients and expression levels of signature genes, a median risk score (RS) was calculated to classify patients into high- and low-risk groups. The high-risk group had a significantly worse prognosis than the low-risk group. An in-depth analysis revealed that TP53 mutations were more prevalent in the high-risk group, and MUC16 mutations were more prevalent in the low-risk group. A gene set enrichment analysis (GSEA) and the CIBERSORT algorithm were used to assess the differences in the significantly enriched pathways and immune microenvironment in the high- and low-risk groups, respectively. The inhibitory concentration (IC50) values of the chemotherapy drugs for GC also varied between the two groups. This study elucidated the unique molecular characteristics of GC subtypes based on the anatomical site and provided a preliminary contribution for the development of precision medicine for GC.

New Horizons in the Diagnosis of Gastric Cancer: The Importance of Selected Toll-like Receptors in Immunopathogenesis Depending on the Stage, Clinical Subtype, and Gender of Newly Diagnosed Patients.

Toll-like receptors (TLRs) play a vital role in the innate immune response, recognizing pathogens and initiating the inflammatory response. Research suggests that TLRs may also have a significant impact on the development and progression of cancers, including gastric cancer (GC). Understanding the role of individual TLRs in the immunopathogenesis of gastric cancer may provide new information necessary to develop more effective diagnostic and therapeutic methods. This study aimed to determine the role of selected TLR-2, -3, -4, and -9 in the immunopathogenesis of patients with newly diagnosed and untreated gastric cancer. The study included 60 newly diagnosed, untreated GC patients and 25 healthy volunteers. The research included analyses assessing the percentage of the tested TLRs on T and B lymphocyte subpopulations using multicolor flow cytometry and assessing their concentration in the serum of the examined patients using ELISA tests. The statistical analyses performed included a comparison of patients in individual stages of gastric cancer, an analysis of the most common clinical subtypes of gastric cancer, and a comparative analysis of differences in the gender of recruited patients. Our studies showed different expression levels of TLR-2, -3, -4, and -9 on T and B lymphocyte subpopulations, as well as their different concentrations in patients' serum. Significant differences in the expression of these receptors were observed depending on the stage of gastric cancer and its clinical subtypes. These differences were also visible in the context of patient gender. The results of our studies suggest that TLR-2, -3, -4, and -9 may play an important role in the immunopathogenesis of gastric cancer. The differential expression of these receptors depending on the stage of the disease, clinical subtype, and gender of patients may have potential diagnostic and therapeutic significance. Further research is necessary to understand better the mechanisms of action of TLRs in gastric cancer and to apply this knowledge in clinical practice.

Subtyping of gastric cancer based on basement membrane genes that stratifies the prognosis, immune infiltration and therapeutic response

Gastric cancer (GC) is highly heterogeneous and prone to metastasis, which are obstacles to the effectiveness of treatment. The basement membrane (BM) acts as a barrier to tumor cell invasion and metastasis. It is critical to investigate the relationship between BM status, metastasis, and patient prognosis. In several large cohorts, we investigated BM gene expression-based molecular classification and risk-prognosis models for GC, examined tumor microenvironment (TME) differences among different molecular subtypes, and developed risk models in predicting prognosis, immunotherapy effectiveness, and chemotherapy resistance. Three GC subtypes (BMclusterA/B/C) based on BM gene expression status were discovered. Each of the three GC subtypes has unique immune infiltration and activated oncogenic signals. Moreover, a 6-gene score (BMscore) predictive model was developed. The low BMscore group had a high tumor mutation burden, high immunogenicity, and low RHOJ expression levels, implying that individuals with GC in this category may be more susceptible to immunotherapy and treatment. The EMT subtype showed a considerably higher BMscore than the other subtypes in the Asian Organization for Research on Cancer (ACRG) molecular classification. Endothelial cells, smooth muscle cells, and fibroblasts may be engaged in regulating BM reorganization in GC progression, according to single-cell transcriptome analyses. In conclusion, we defined a novel molecular classification of GC based on BM genes, developed a prognostic risk model, and elucidated the cell subpopulations involved in BM remodeling at the single-cell level. This study has deepened the understanding of the relationship between GC metastasis and BM alterations, achieved prognostic stratification, and guided therapy.

Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study

Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers. Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR>1) at an α-level of 0.05 for obesity (BMI ≥30kg/m2) vs. normal weight (BMI 18.5-24.9kg/m2) or per 5kg/m2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related. After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5kg/m2 higher BMI was 1.17 (1.15-1.20) in men and 1.13 (1.11-1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22-1.26) in men and 1.12 (1.11-1.13) in women for established obesity-related cancers (84,384 cases). This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings. Swedish Research Council, Swedish Cancer Society, Mrs. Berta Kamprad's Cancer Foundation, Crafoord Foundation, Cancer Research Foundation at the Department of Oncology, Malmö University Hospital, and China Scholarship Council.

Mitochondrial dysregulation is a key regulator of gastric cancer subtype carcinogenesis

Mitochondrial dysregulation is a key regulator of gastric cancer subtype carcinogenesis

Glycolysis-related genes predict prognosis and indicate immune microenvironment features in gastric cancer.

Gastric cancer (GC) is a major contributor to cancer-related mortality. Glycolysis plays a pivotal role in tumor microenvironment (TME) reprogramming. In this research, the functions of glycolysis-associated genes (GRGs) were evaluated to predict the outcome and reveal the characteristics of the immune microenvironment in individuals with stomach cancer. The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) cohort provided gene expression and clinical data for gastric cancer (GC) patients, which were further authenticated using datasets sourced from the Gene Expression Omnibus (GEO). By referencing the Molecular Signatures Database (MSigDB), a total of 326 GRGs were pinpointed. The various subtypes of GC were outlined through consensus clustering, derived from the expression patterns of these GRGs. Utilizing multivariate Cox regression analysis, a multigene risk score model was formulated. Both the CIBERSORT and ESTIMATE algorithms played a pivotal role in assessing the immune microenvironment. To delve into the biological functions of the key genes, wound healing, transwell invasion, and MTT assays were conducted. Based on the expression patterns of GRGs, patients were categorized into two distinct groups: the metabolic subtype, designated as cluster A, and the immune subtype, labeled as cluster B. Patients belonging to cluster B exhibited a poorer prognosis. A prognostic risk score model, formulated upon the expression levels of six key GRGs - ME1, PLOD2, NUP50, CXCR4, SLC35A3, and SRD35A3 - emerged as a viable tool for predicting patient outcomes. The downregulation of CXCR4 notably diminished the glycolytic capacity of gastric cancer (GC) cells, alongside their migratory, invasive, and proliferative capabilities. Intriguingly, despite the adverse prognostic implications associated with both the immune subtype (cluster B) and the high-risk cohort, these groups exhibited a favorable immune microenvironment coupled with elevated expression of immune checkpoint genes. Our investigations revealed a positive correlation between high CXCR4 expression and low ME1 expression with the infiltration of CD8+ T cells, as well as an enhanced responsiveness to treatment with an anti-PD-1 immune checkpoint inhibitor. In this study, we discovered that the expression profiles of GRGs hold the potential to forecast the prognosis of gastric cancer (GC) patients, thereby possibly aiding in clinical treatment decision-making.

Differences in Prevalence of Histologic Gastric Cancer Subtypes Between Mestizo and Mayan Populations in Guatemala.

Although the intestinal subtype of gastric cancer (GC) is most prevalent around the world, a relatively high prevalence of the diffuse subtype has been reported in some populations of Central American countries, including Guatemala. This study aimed to investigate whether differences exist in the prevalence of the two GC subtypes in the two main ethnic groups in Guatemala, namely Mayan and Mestizo (known as Ladino in Guatemala), between whom significant socioeconomic disparities exist, and to determine whether there is an association with Helicobacter pylori/CagA seropositivity. Participants included 65 patients with GC and 135 age-/sex-matched controls. Data on ethnicity, H. pylori and CagA seropositivity status, as well as tumor subtype (diffuse or intestinal) were collected. Logistic regression models were fitted to examine the relationship between predictor variables (age, sex, ethnicity, H. pylori, and CagA) and the binary response variable (tumor type). Model selection was based on the Akaike information criterion. The prevalence of diffuse GC was found to be significantly higher in the Mayan compared with the Mestizo population in Guatemala. Although seropositivity for CagA was significantly higher in patients with GC, there were no significant differences between the two GC subtypes. This study suggests that there are differences in the prevalence of intestinal and diffuse GC histologic subtypes between the two main ethnic groups in Guatemala. Further studies are warranted, given the potential higher prevalence of the more severe GC subtype in the most vulnerable population.

Current development of molecular classifications of gastric cancer based on omics (Review).

Gastric cancer (GC) is a complex and heterogeneous disease with significant phenotypic and genetic variation. Traditional classification systems rely mainly on the evaluation of clinical pathological features and conventional biomarkers and might not capture the diverse clinical processes of individual GCs. The latest discoveries in omics technologies such as next‑generation sequencing, proteomics and metabolomics have provided crucial insights into potential genetic alterations and biological events in GC. Clustering strategies for identifying subtypes of GC might offer new tools for improving GC treatment and clinical trial outcomes by enabling the development of therapies tailored to specific subtypes. However, the feasibility and therapeutic significance of implementing molecular classifications of GC in clinical practice need to addressed. The present review examines the current molecular classifications, delineates the prevailing landscape of clinically relevant molecular features, analyzes their correlations with traditional GC classifications, and discusses potential clinical applications.

Endoscopic Surveillance of Gastric Intestinal Metaplasia: A Retrospective Cohort Study.

Gastric intestinal metaplasia (GIM) is a precancerous condition. Limited data exist on real-world clinical practice relative to guidelines. The aim of this study was to evaluate adherence to GIM risk stratification and identify factors associated with follow-up endoscopy. We conducted manual chart review of patients with histologically confirmed GIM at an urban, tertiary medical center were identified retrospectively and details of their demographics, Helicobacter pylori, biopsy protocol, endoscopic/histologic findings, and postendoscopy follow-up were recorded. Multivariable logistic regression was used to identify factors independently associated with follow-up endoscopy. Among 253 patients, 59% were female, 37% non-Hispanic White (NHW), 26% Hispanic, 16% non-Hispanic Black (NHB). The median age at index endoscopy was 63.4 years (IQR: 55.9 to 70.0), with median follow-up of 65.1 months (IQR: 44.0 to 72.3). H. pylori was detected in 21.6% patients at index EGD. GIM extent and subtype data were frequently missing (22.9% and 32.8%, respectively). Based on available data, 26% had corpus-extended GIM and 28% had incomplete/mixed-type GIM. Compared with NHW, Hispanic patients had higher odds of follow-up EGD (OR=2.48, 95% CI: 1.23-5.01), while NHB patients had 59% lower odds of follow-up EGD (OR=0.41, 95% CI: 0.18-0.96). Corpus-extended GIM versus limited GIM (OR=2.27, 95% CI: 1.13-4.59) was associated with follow-up EGD, but GIM subtype and family history of gastric cancer were not. We observed suboptimal risk stratification among patients with GIM and notable race and ethnic disparities with respect to endoscopic surveillance. Targeted interventions are needed to improve practice patterns and mitigate observed disparities.