This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC.

We found that amylin expression was reduced in GC compared to adjacent normal gastric tissues and that elevated amylin expression was negatively correlated with adverse pathological factors (p < 0.05). Additionally, we demonstrated that amylin impeded the growth, invasion, migration, and colony formation of GC cells and suppressed the epithelial-to-mesenchymal transformation of these cells (p < 0.05). Tumour xenograft model experiments confirmed the tumour-suppressive effect of amylin in subcutaneous tumours in nude mice (p < 0.05). Transcriptome sequencing (RNA-seq) revealed that amylin significantly down-regulated CCN1 gene expression in GC cells (p < 0.001). Further intervention targeting CCN1 verified its significance as a target of amylin's anti-carcinogenic function in GC. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that amylin exerted its oncogenic effects by inhibiting the PI3K/Akt signalling pathway (p < 0.05).

Our findings demonstrate that amylin plays a crucial role in suppressing gastric cancer progression by targeting CCN1 and inhibiting the PI3K/Akt signalling pathway. These results suggest that amylin could serve as a potential therapeutic agent for GC treatment.

Gastric cancer (GC) poses a major global health challenge, underscoring the need for advanced diagnostic and therapeutic approaches. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators in GC, with their dysregulated expression driving key processes such as tumorigenesis, metastasis, immune evasion, and chemoresistance. The functional diversity of ncRNAs across different GC molecular subtypes highlights their potential as biomarkers for improved subtype classification and patient stratification. Beyond their diagnostic value, ncRNAs demonstrate critical regulatory functions in tumor biology, establishing these RNA molecules as promising targets for therapeutic development. Strategies based on RNA hold considerable promise for addressing critical challenges such as immune escape and drug resistance by modulating key signaling pathways. These approaches can enhance immune responses, reprogram the tumor microenvironment, and reverse resistance mechanisms that compromise treatment efficacy, thereby improving clinical outcomes. Although ncRNAs represent a promising frontier in GC precision medicine, further research is required to fully harness their clinical potential.

Immune checkpoint inhibitors (ICIs) + chemotherapy became standard her2-GC first line treatment.

The aim of this study is to investigate whether ICIs + chemo provides benefit for patients with low programmed death-ligand 1 (PD-L1) expression.

This study is a systematic review and meta-analysis.

We searched PubMed, Embase, Web of Science, and Cochrane Library as well as the 2019 to 2024 Annual Meetings of the European Society for Medical Oncology, the American Association for Cancer Research, the American Society of Clinical Oncology (ASCO), and the ASCO Symposium on Gastrointestinal Oncology (ASCO-GI) and the ClinicalTrials.gov database.

This systematic review included phase III randomized controlled trials comparing first-line immunotherapy combined with chemotherapy versus chemotherapy alone in advanced gastric cancer. KMSubtraction was used to estimate survival data for those trials that did not report data for the PD-L1 low-expression population.

We included a total of nine randomized clinical trials. In patients with combined positive score (CPS) < 1 and CPS < 5, monoclonal antibody + chemotherapy did not show an improvement in overall survival (OS) or progression-free survival (PFS) (CPS < 1 OS: hazard ratio (HR) = 0.91, 95% CI: 0.77-1.08; PFS: HR = 0.88, 95% CI: 0.73-1.07. CPS < 5 OS: HR = 0.92, 95% CI: 0.79-1.08; PFS: HR = 0.78, 95% CI: 0.53-1.14). However, in trials using dual antibodies, patients with PD-L1 CPS < 5 achieved improvements in PFS (HR = 0.64, 95% CI: 0.52-0.80). In trials using tumor area positivity (TAP) scoring, the subgroup with TAP < 5% did not achieve benefits in OS or PFS from immunotherapy plus chemotherapy (OS: HR = 0.92, 95% CI: 0.75-1.13; PFS: HR = 0.91, 95% CI: 0.74-1.13).

Our study results indicate that in the first-line treatment of advanced gastric cancer, monoclonal antibody combined with chemotherapy does not provide a survival benefit compared to chemotherapy alone for patients with low PD-L1 expression. However, it is noteworthy that in the COMPASSION-15 trial, patients with CPS < 5 achieve significant improvements in OS and PFS, which may be related to the bispecific antibodies and needs to be validated by further studies.

This study was registered in PROSPERO (CRD42024568972).

The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.

Gastric cancer (GC) is a prevalent digestive system tumor, the fifth most diagnosed cancer worldwide, and a leading cause of cancer deaths. GC is distinguished by its pronounced heterogeneity and a dynamically evolving tumor microenvironment (TME). The lack of accurate disease models complicates the understanding of its mechanisms and impedes the discovery of novel drugs. A growing body of evidence suggests that GC organoids, developed using organoid culture technology, preserve the genetic, phenotypic, and behavioral characteristics. GC organoids hold significant potential for predicting treatment responses in individual patients. This review provides a comprehensive overview of the current clinical treatment strategies for GC, as well as the history, construction and clinical applications of organoids. The focus is on the role of organoids in simulating the TME to explore mechanisms of immune evasion and intratumoral microbiota in GC, as well as their applications in guiding clinical drug therapy and facilitating novel drug screening. Furthermore, we summarize the limitations of GC organoid models and underscore the need for continued technological advancements to benefit both basic and translational oncological research.

Most patients with gastric cancer (GC) exhibit microsatellite stability, yet comprehensive subtyping for prognostic prediction and clinical treatment decisions for microsatellite-stable GC is lacking. In this work, RNA-sequencing gene expression data and clinical information of patients with microsatellite-stable GC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed several machine learning methods to develop and validate a signature based on immune-related genes (IRGs) for subtyping patients with microsatellite-stable GC. Moreover, 2 deep learning models based on the Vision Transformer (ViT) architecture were developed to predict GC tumor tiles and identify microsatellite-stable GC subtypes from digital pathology slides. Microsatellite status was evaluated by immunohistochemistry, and prognostic data as well as hematoxylin and eosin whole-slide images were collected from 105 patients with microsatellite-stable GC to serve as an independent validation cohort. A signature comprising 5 IRGs was established and validated, stratifying patients with microsatellite-stable GC into high-risk (microsatellite-stable-HR) and low-risk (microsatellite-stable-LR) groups. This signature demonstrated consistent performance, with areas under the receiver operating characteristic curve (AUC) of 0.65, 0.70, and 0.70 at 1, 3, and 5 years in the TCGA cohort, and 0.70, 0.60, and 0.62 in the GEO cohort, respectively. The microsatellite-stable-HR subtype exhibited higher levels of tumor immune dysfunction and exclusion, suggesting a greater potential for immune escape compared with the microsatellite-stable-LR subtype. Moreover, the microsatellite-stable-HR/LR subtypes showed differential sensitivities to various therapeutic drugs. Leveraging morphologic differences, the tumor recognition segmentation model achieved an impressive AUC of 0.97, whereas the microsatellite-stable-HR/LR identification model effectively classified microsatellite-stable-HR/LR subtypes with an AUC of 0.94. Both models demonstrated promising results in classifying patients with microsatellite-stable GC in the external validation cohort, highlighting the strong ability to accurately differentiate between microsatellite-stable GC subtypes. The IRG-related microsatellite-stable-HR/LR subtypes had the potential to enhance outcome prediction accuracy and guide treatment strategies. This research may optimize precision treatment and improve the prognosis for patients with microsatellite-stable GC.

Gastric cancer (GC) is a molecularly heterogeneous disease with diverse clinical outcomes. Traditional classifications lack predictive accuracy, necessitating alternative molecular subtyping approaches for effective prognosis prediction. The Asian Cancer Research Group (ACRG) molecular subtypes, combined with immune-associated PD-L1 expression, offer a promising framework to predict patient outcomes and potentially guide treatment strategies in GC.

This study retrospectively analyzed 1007 primary GC patients who underwent surgical resection between January 2017 and June 2019 at the Fourth Hospital of Hebei Medical University. Comprehensive immunohistochemical and fluorescent PCR-capillary electrophoresis analyses were conducted to determine ACRG molecular subtypes (microsatellite instability [MSI], microsatellite stability with epithelial-mesenchymal transition [MSS/EMT], MSS/TP53+, and MSS/TP53-) and PD-L1 expression. We assessed the relationship between these classifications and various clinicopathological parameters, including survival outcomes, using Cox regression and Kaplan-Meier analysis.

The ACRG subtypes showed significant associations with clinicopathological features, including tumor invasion depth, Lauren classification, and HER2 status. The MSI subtype (6.7% of cases) was associated with higher PD-L1 positivity and a favorable prognosis, whereas the EMT subtype had the lowest 5-year survival rate (34.55%) and was predominantly linked to diffuse-type histology. PD-L1 positivity correlated with worse survival outcomes, with independent predictive value alongside ACRG subtypes (HR for PD-L1 = 1.759, p = 0.001; HR for ACRG = 5.144, p < 0.001).

The combination of ACRG molecular subtyping and PD-L1 expression serves as an effective predictor of GC prognosis, facilitating tailored clinical decision-making. The ACRG-PD-L1 classification system offers a practical, cost-effective approach for routine clinical application, providing critical insight into GC heterogeneity. Further multicenter studies are needed to validate these findings and explore the impact of ACRG subtypes on therapy responses, particularly in immunotherapy settings.

Despite improvements in therapeutic approaches, the mortality rate of gastric cancer (GC) remains unacceptably high. Evidence suggests that FXYD domain containing ion transport regulator 6 (FXYD6) is downregulated in GC. However, its exact function and the molecular mechanism in GC are still unclear. FXYD6 expression in different cell lines was estimated using RT-qPCR. Western blotting was employed for protein expression detection. Cell counting kit-8 assay, colony formation assay, and flow cytometry were implemented to assess GC cell viability, proliferation, and apoptosis, respectively. Bioinformatics analysis as well as chromatin immunoprecipitation and luciferase reporter assays were utilized for verifying FXYD6 interaction with the transcription factor Krüppel-like factor 10 (KLF10). The results showed that FXYD6 displayed a decreased level in GC cell lines. Impaired proliferative ability and enhanced apoptotic capacity were observed in GC cells overexpressing FXYD6. KLF10 expression is positively correlated with FXYD6 expression in GC samples. KLF10 binds to the FXYD6 promoter to enhance its transcription. FXYD6 depletion counteracted KLF10 upregulation-triggered reduction in GC cell proliferation and elevation in apoptosis. In conclusion, KLF10 activates FXYD6 transcription, thereby impeding GC cell proliferation and promoting cell apoptosis.

The efficacy of perioperative chemotherapy for deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) gastric cancer (GC) remains controversial.

This study was preregistered with the PROSPERO platform (CRD42023494276), and studies comparing perioperative chemotherapy with surgery alone in resectable dMMR/MSI-H GC were included. Hazard ratios (HRs) and their 95% confidence intervals (CIs) of survival outcomes were extracted. A random-effects model was used in the pooled analysis.

Twenty-two studies, which encompassed approximately 1600 patients with dMMR/MSI-H GC, were included. The results indicated that perioperative chemotherapy does not significantly improve overall survival (OS) (HR, 0.85; 95% CI, 0.58-1.26) and disease-free survival (DFS) (HR, 0.77; 95% CI, 0.53-1.12) in dMMR/MSI-H GC. In the subgroup analysis, adjuvant chemotherapy was not associated with improved OS (HR, 0.83; 95% CI, 0.50-1.37) but was associated with improved DFS (HR, 0.64; 95% CI, 0.43-0.96). However, the benefit of adjuvant chemotherapy for DFS was not significant in the pooled analysis of multivariable-adjusted results. Similar results were observed for neoadjuvant chemotherapy (OS: HR, 0.84; 95% CI, 0.44-1.57; DFS: HR, 1.13; 95% CI, 0.50-2.53). Additionally, stage stratification analysis demonstrated no significant survival benefit of adjuvant chemotherapy for stage II (OS: HR, 0.77; 95% CI, 0.31-1.90) or stage III (OS: HR, 0.72; 95% CI, 0.36-1.46) dMMR/MSI-H GC.

Despite indications that adjuvant chemotherapy may improve DFS in the subgroup analysis, this benefit was not sustained in multivariate assessments. Overall, the pooled results indicate that perioperative chemotherapy does not significantly improve OS or DFS in patients with resectable dMMR/MSI-H GC, and therefore such treatment may be spared in these patients.

Combinations of immune checkpoint inhibitors (ICIs) and chemotherapy have become the standard first-line treatment for human epidermal growth factor receptor 2 (HER-2)-negative advanced gastric cancer. However, primary resistance remains a challenge, with no effective biomarkers available for its prediction. This retrospective study explores the relationship between the baseline inflammatory burden index (IBI) and primary resistance in such context.

We analyzed 62 patients with HER-2-negative advanced gastric cancer who received ICIs and chemotherapy as their first-line treatment. The IBI was calculated as follows: C-reactive protein (mg/L) × neutrophil count (10³/mm³)/lymphocyte count (10³/mm³). Based on disease progression within 6 months, patients were categorized into the primary resistant or the control group. We compared baseline characteristics and IBI scores between the groups and assessed the predictive value of the IBI using the receiver operating characteristic curve. Both univariate and multivariate binary logistic regression analyses were conducted to identify factors influencing primary resistance.

Nineteen patients were included in the primary resistance group, and forty-three patients were included in the control group. The IBI was significantly higher in the resistant group compared to the control group (P<0.01). The area under the curve for the IBI was 0.82, indicating a strong predictive value. Multivariate analysis identified the IBI as an independent predictor of primary resistance (P=0.014).

The baseline IBI holds promise as a predictor of primary resistance to combined ICIs and chemotherapy in patients with HER-2-negative advanced gastric cancer.

Stomach adenocarcinoma (STAD) with microsatellite instability (MSI) is associated with a better prognosis compared to Non-MSI. This study aims to elucidate the differences in the tumor microenvironment (TME) of MSI and explore its underlying mechanisms in STAD.

TME differences between MSI and Non-MSI were analyzed using single-cell RNA sequencing (MSI = 7, Non-MSI = 19) and bulk RNA sequencing (MSI = 39, Non-MSI = 198). Differentially expressed genes (DEGs) were used to identify enriched pathways and hub genes. TNFSF9 expression was validated by immunohistochemistry (IHC) on 23 STAD sections (MSI = 13, Non-MSI = 10) and confirmed in tumor epithelial cells using SNU-1 (MSI) and AGS (Non-MSI) cell lines through quantitative polymerase chain reaction (qPCR) and Western blot (WB).

The results showed MSI was significantly associated with a better prognosis (P < 0.05). Within the TME, MSI was associated with a higher abundance of antigen-presenting cells, including M1 macrophages (40.1% vs. 27.9%) and activated dendritic cells (22.1% vs. 10.5%), as well as pro-inflammatory Th1-like CD4⁺ T cells (15% vs. 11%). However, MSI also showed an increase in exhausted T cells, indicating a complex immune landscape. Signaling pathway and cell communication analyses revealed an enrichment of cytokine-related pathways in MSI. Hub gene analysis revealed that TNFSF9 was predominantly expressed in stromal cells and partially in tumor epithelial cells in MSI, with its upregulation further confirmed through IHC, qPCR, and WB. Correlation analysis demonstrated a positive relationship between TNFSF9 expression and the abundance of M1 macrophages.

These findings provide new insights into the TME of MSI in STAD, emphasizing the significant role of TNFSF9 in shaping MSI-specific TME, enhancing immunotherapy efficacy, and improving patient survival.

Advanced gastric adenocarcinoma (GAC) carries a poor prognosis. Targeted therapy in GAC has traditionally been limited to anti-human epidermal growth factor receptor-2 and anti-vascular endothelial growth factor agents. Recent years have brought immune checkpoint therapy to the GAC treatment landscape. However, continued discovery of targeted therapy in GAC is needed. Claudins, transmembrane proteins located in tight junctions of epithelial and endothelial cells, help regulate cellular polarity. Claudin dysregulation has been linked to cancers and other diseases. Claudin 18.2 specifically has become a new novel and exciting biomarker for GAC. Many agents are in the investigative pipeline, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric T-cell therapy. Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab's place in therapy along with other agents being explored.

Immunotherapy has surfaced as a promising therapeutic modality for gastric cancer (GC). A comprehensive review of advancements, current status, and research trends in GC immunotherapy is essential to inform future investigative efforts.

To delineate the trends, advancements, and focal points in immunotherapy for GC.

We performed a bibliometric analysis of 2906 articles in English concerning GC immunotherapy published from 2000 to December 20, 2023, indexed in the Web of Science Core Collection. Data analysis and visualization were facilitated by CiteSpace (6.1.6R), VOSviewer v.1.6.17, and GraphPad Prism v8.0.2.

There has been an increase in the annual publication rate of GC immunotherapy research. China leads in publication volume, while the United States demonstrates the highest citation impact. Fudan University is notable for its citation frequency and publication output. Co-citation analysis and keyword frequency revealed and highlighted a focus on GC prognosis, the tumor microenvironment (TME), and integrative immunotherapy with targeted therapy. Emerging research areas include gastroesophageal junction cancer, adoptive immunotherapy, and the role of Treg cell in immunotherapy.

GC immunotherapy research is an expanding field attracting considerable scientific interest. With the clinical adoption of immunotherapy in GC, the primary goals are to enhance treatment efficacy and patient outcomes. Unlike hematological malignancies, GC's solid TME presents distinct immunological challenges that may attenuate the cytotoxic effects of immune cells on cancer cells. For instance, although CAR-T therapy is effective in hematological malignancies, it has underperformed in GC settings. Current research is centered on overcoming immunosuppression within the TME, with a focus on combinations of targeted therapy, adoptive immunotherapy, Treg cell dynamics, and precise prognosis prediction in immunotherapy. Additionally, immunotherapy's role in treating gastroesophageal junction cancer has become a novel research focus.

Glycolysis is recognized as a central metabolic pathway in the neoplastic evolution of gastric cancer, exerting profound effects on the tumor microenvironment and the neoplastic growth trajectory. However, the identification of key glycolytic genes that significantly affect gastric cancer prognosis remains underexplored. In this work, five machine-learning algorithms were used to elucidate the intimate association between the glycolysis-associated gene phosphofructokinase fructose-bisphosphate 3 (PFKFB3) and the prognosis of gastric cancer patients. Validation across multiple independent datasets confirmed the prognostic significance of PFKFB3. Further, we delved into the functional implications of PFKFB3 in modulating immune responses and biological processes within gastric cancer patients, as well as its broader relevance across multiple cancer types. Results underscore the potential of PFKFB3 as a prognostic biomarker and therapeutic target in gastric cancer. Our project can be found at https://github.com/PiPiNam/ML-GCP .

Gastroesophageal carcinomas, including gastroesophageal adenocarcinoma (GEA) and esophageal squamous cell carcinoma (ESCC), pose a global health challenge due to their heterogeneity. The approach to diagnosis and treatment should first differentiate between GEA and ESCC. Over the past decade, therapies for metastatic or advanced GEA/ESCC have expanded, with several new therapeutic targets alongside trastuzumab for metastatic HER2-positive GEA. Four key biomarkers are essential for targeted therapy: HER2 overexpression/amplification, deficient mismatch repair/microsatellite instability (dMMR/MSI), PD-L1, and Claudin18.2 expression. Immunohistochemistry is the recommended method for these biomarkers evaluation. In addition, the assessment of biomarkers like FGFR2b is likely to become routine in the near future. Experts from the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have formed a consensus to optimize biomarker detection and usage in clinical practice. Their recommendations aim to improve personalized treatment strategies for GEA and ESCC patients, integrating new diagnostic insights into routine care.

Gastric cancer (GC) remains a leading cause of cancer-related mortality, with over one million new cases and 769,000 deaths reported in 2020. Despite advancements in chemotherapy, surgery, and targeted therapies, delayed diagnosis due to overlooked early symptoms leads to poor prognosis.

We integrated bulk RNA sequencing and single-cell RNA sequencing datasets from TCGA, GEO, and OMIX001073, employing normalization, batch effect correction, and dimensionality reduction methods to identify key cell populations associated with GC invasion and epithelial-mesenchymal transition (EMT), as well as analyze the tumor immune microenvironment.

Our analysis identified the MUC5AC+ malignant epithelial cell cluster as a significant player in GC invasion and EMT. Cluster 1, representing this cell population, exhibited higher invasion and EMT scores compared to other clusters. Survival analysis showed that high abundance in cluster 0 correlated with improved survival rates (P=0.012), whereas cluster 1 was associated with poorer outcomes (P=0.045). A prognostic model highlighted ANXA5 and GABARAPL2 as two critical genes upregulated in GC tumors. High-risk patients demonstrated increased immune cell infiltration and worse prognosic. Analysis of tumor mutation burden (TMB) indicated that patients with low TMB in the high-risk group had the worst prognosis. Wet-lab validation experiments confirmed the oncogenic role of ANXA5, showing its facilitation of cell proliferation, invasion, and migration while suppressing apoptosis.

This study offers novel insights into the subpopulations of malignant epithelial cells in GC and their roles in tumor progression. It provides a prognostic model and potential therapeutic targets to combat GC, contributing crucial understanding to the fundamental mechanisms of drug resistance in gastrointestinal cancers.

This review addresses the current treatment paradigm and new advancements in the management of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) esophagogastric cancer (EGC).

While chemotherapy and surgery remain the cornerstone of EGC treatment, MSI-H/dMMR tumors harbor high tumor mutational burden and represent a subset of patients who benefit from immune checkpoint inhibitors (ICI). ICI has been incorporated in the front line setting with and without chemotherapy for advanced disease. Recently, ICI has been studied in the perioperative setting for resectable disease. Though perioperative ICI results in improved response rates, it is not yet clear whether this translates to a survival benefit. Despite high response rates with ICI in this patient population, many do not respond to therapy, representing a major challenge in treatment. Preclinical studies have highlighted potential mechanisms of resistance which will guide drug development and clinical trials.

Long non-coding RNAs (lncRNAs) in extracellular vesicles (EVs) have been confirmed as effective non-invasive biomarkers for multiple diseases. However, their expression and clinical value in gastric cancer (GC) remain poorly understood.

Serum EV RNA was extracted from four patients with GC and four healthy controls, followed by high-throughput RNA sequencing. LncRNAs were further validated in training and validation sets using quantitative real-time reverse transcription polymerase chain reaction.

A total of 37,684 lncRNAs were obtained, and 10 lncRNAs were selected based on the criteria (P < 0.05 and |log2FoldChange| ≥1). Serum EV lncRNA RMRP, RPPH1, and linc-ROR were significantly higher in patients with GC than in those with chronic gastritis, atypical hyperplasia, or healthy control (all P < 0.05). Three lncRNAs were also significantly correlated with tumor diameter, lymphatic metastasis, distal metastasis, and TNM stage (all P < 0.05). The area under the curve (AUC) values for lncRNA RMRP, RPPH1, and linc-ROR were 0.727, 0.774, and 0.811, respectively. Corresponding sensitivity and specificity were 63.4% and 85.4%, 50.7% and 89.6%, and 78.5% and 66.7%. The combination of these three lncRNAs with carcinoembryonic antigen (CEA) yielded an AUC of 0.909, with a sensitivity and specificity of 83.3% each. Furthermore, high EV linc-ROR and RMRP expression levels were associated with worse disease-free survival and overall survival (OS). Univariate and multivariate Cox regression analyses confirmed that linc-ROR was the only independent prognostic factor for GC. Finally, the lncRNA-miRNA-mRNA network showed that three lncRNAs were predicted to interact with 15 miRNAs and 69 mRNAs. In addition, lncRNA RMRP and linc-ROR were correlated with immune cell infiltration, including neutrophils, central memory CD4 T cells, macrophage, and natural kill T cells.

EV lncRNAs are prospective biomarker and correlated with immune cell infiltration in GC. It provides a foundation for the development of serum EV-targeted novel biomarkers and immunotherapy targets of GC.

The mismatch repair (MMR) system plays a crucial role in the maintenance of DNA replication fidelity and genomic stability. The clinical value of the MMR molecular marker as an immunotherapy for advanced solid tumors has been documented. However, this therapy is not effective in some patients. This study aimed to develop an MMR-related molecular prognostic model for identifying appropriate populations of stomach adenocarcinoma (STAD) for better treatment outcome. The MMR genes expression data were downloaded from TCGA and CCLE databases. The expression of four MMR genes, construction of a prognostic risk model, and assessment of immune infiltration in STAD were performed using Xiantao online tool. GEPIA2 was used to explore the association of MMR genes expression with clinical stage and overall survival. The frequency and prognostic value of MMR genes in STAD were conducted on the cBioPortal. The MLH1 co-expression network was established based on the LinkedOmics database. This study found that the expression of MSH2, MSH6 and PMS2 was up-regulated in STAD tissues. Moreover, differential MMR genetic expression levels were not significantly correlated with the clinical stages of STAD. Besides, no significant difference in PFS or OS was observed in STAD patients with or without MMR genetic alteration. Moreover, MLH1 and MSH2 were used to establish a prognostic risk model. The immune infiltration levels of most immune cells were upregulated in the high-risk group with elevated expression of PDCD1 and low TMB score. Finally, we found that MLH1 was an independent predictor of STAD prognosis among the four MMR genes. An MMR-related prognostic model for STAD was constructed based on genes. This model provides a new therapeutic concept for the diagnosis and treatment of STAD.

Previous studies have demonstrated that TRIB3 plays a carcinogenic role in tumor progression. However, the exploration of TRIB3 at the pan-cancer level has not been reported.

This study aimed to conduct a comprehensive pan-cancer analysis of TRIB3.

We explored the expression pattern and functional mechanism of TRIB3 on the basis of multiple databases.

We first explored the expression level of TRIB3 in the TCGA database. Then, the receiver operation characteristic curve (ROC), Kaplan-Meier plotter, and Cox regression were used to estimate the diagnostic and prognostic value of TRIB3, respectively. We also explored the relationship between TRIB3 and the infiltration of tumor immune cells, as well as the expression of immune checkpoint molecules. Gene enrichment and protein interaction network analysis were carried out to identify possible carcinogenic molecular mechanisms and functional pathways. Finally, we compared the non-promoter region methylation of TRIB3 in normal and tumor tissues and explored potential systems with unique functions in TRIB3-mediated tumorigenesis.

The expression level of TRIB3 was elevated in multiple tumor types, and the high expression of TRIB3 was associated with poor prognosis. TRIB3 had a higher frequency of genetic changes in several tumors and showed varying trends in TRIB3 methylation levels. Additionally, high expression of TRIB3 was also associated with infiltration of cancer-related fibroblasts and different types of immune cells and was positively correlated with the expression of immune checkpoint molecules. Furthermore, gene enrichment analysis suggested that TRIB3 may play a role in the malignant progression of cancer by participating in protein post-translational modifications and activating transcription initiation factors.

Our pan-cancer analysis provided the potential carcinogenic role of TRIB3 in tumors and verified a promising target for clinical immune treatment.

Significant challenges persist in the early identification of microsatellite instability (MSI) within current clinical practice. In recent years, with the growing utilization of machine learning (ML) in the diagnosis and management of gastric cancer (GC), numerous researchers have explored the effectiveness of ML methodologies in detecting MSI. Nevertheless, the predictive value of these approaches still lacks comprehensive evidence. Accordingly, this study was carried out to consolidate the accuracy of ML in the prompt detection of MSI in GC.

PubMed, the Cochrane Library, the Web of Science, and Embase were retrieved up to March 20, 2024. The risk of bias in the encompassed studies was evaluated utilizing a risk assessment tool for predictive models. Models were then subjected to subgroup analysis based on the modeling variables.

A total of 12 studies, encompassing 11,912 patients with GC, satisfied the predefined inclusion criteria. ML models established in these studies were primarily based on pathological images, clinical features, and radiomics. The results suggested that in the validation sets, the pathological image-based models had a synthesized c-index of 0.86 [95 % CI (0.83-0.89)], with sensitivity and specificity being 0.86 [95 % CI (0.76-0.92)] and 0.83 [95 % CI (0.78-0.87)], respectively; radiomics feature-based models achieved respective values of 0.87 [95 % CI (0.81-0.92)], 0.77 [95 % CI (0.70-0.83)] and 0.81 [95 % CI (0.74-0.87)]; radiomics feature-based models + clinical feature-based models achieved respective values of 0.87 [95 % CI (0.81-0.93)], 0.78 [95 % CI (0.70-0.84)] and 0.79 [95 % CI (0.69-0.86)].

ML has demonstrated optimal performance in detecting MSI in GC and could serve as a prospective early adjunctive detection tool for MSI in GC. Future research should contemplate minimally invasive or non-invasive, readily collectible, and efficient predictors to augment the predictive accuracy of ML.

Poly (ADP-ribose) polymerase family member 11 (PARP11) has important immune regulatory functions in viral infection and tumor immune response. Particularly, PARP11 showed protumor activities in multiple preclinical murine models. However, no systematic pan-cancer analysis has been conducted to explore PARP11 function. In this study, we used multiple databases to assess PARP11 expression, which is associated with clinical outcomes, immune checkpoint factors, prognostic significance, genomic characteristics, and immunological aspects. The analysis revealed varying expression levels of PARP11 across different cancer types and a significant correlation between its expression and immune cell infiltration. Insights from the CellMiner database suggest a strong link between PARP11 expression and sensitivity to anticancer drugs, highlighting its potential as a therapeutic target. Moreover, PARP11 expression correlates with patient survival during anti-PD1 and anti-CTLA4 treatments, suggesting that PARP11 would be a predictor of immune checkpoint inhibitor treatment. In summary, PARP11 would be a potential immunoregulatory target and a diagnosis and prognosis marker for certain types of cancers. The detailed mechanisms of PARP11 in tumor immune responses need to be further investigated.

The occurrence of immune-related adverse events (irAEs) seemed to be associated with better outcomes in advanced gastric cancer (AGC) patients. However, research focusing on the impact of the single-organ irAE (uni-irAE) or multi-organ irAEs (multi-irAEs) on the AGC outcome is relatively limited. In this study, we investigated individually the impact of the different irAEs on AGC survival as well as the co-occurrence patterns of multi-irAEs.

The uni-irAE, multi-irAEs, and non-irAE were identified based on National Comprehensive Cancer Network (NCCN) guidelines. ICI efficacy for the disease control rate (DCR) and the objective response rate (ORR) was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The association for the irAEs with progression-free survival (PFS) or overall survival (OS) was analyzed using the Kaplan-Meier method and Cox regression model. We also performed pairwise correlation analysis to identify co-occurrence patterns of multi-organ irAEs.

A total of 288 patients including 175 non-irAE, 73 uni-irAE, and 40 multi-irAE patients were evaluated for their association with AGC outcome. The irAEs patients displayed higher DCR (78.8% vs. 67.4%, p=0.037) when compared with those of non-irAE patients, and both uni-irAE patients (82.2% vs. 67.4%, p=0.019) and multi-irAE patients (72.5% vs. 67.4%, p=0.534) showed higher DCR than that of non-irAE patients. The multivariate analyses revealed that multi-irAEs was an independent risk factor for PFS (hazard ratio [HR] of 0.63, 95% confidence interval [CI] 0.41~0.96, p=0.031) and OS (HR 0.47, 95% CI 0.29~0.76, p=0.002), whereas the survival association for uni-irAE was not obtained. The analysis of the co-occurrence patterns for multi-irAEs revealed that the thyroid, adrenal gland, heart, skin, and lung irAEs exhibited a high risk of co-occurrence of multi-irAEs. The multivariate Cox regression analysis for organ-specific irAEs revealed that patients experiencing thyroid, adrenal gland, and skin irAEs had favorable survival outcomes compared with those without these irAEs.

Multi-irAEs and some organ-specific irAEs can be used as predictive indicators for ICI treatment efficacy in AGC patients. The thyroid, adrenal gland, heart, skin, and lung irAEs are often accompanied by multi-irAE occurrence.

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-β) superfamily and is related to metabolism, injury, and aging. GDF15 has both tumor-promoting and tumor-suppressing effects. However, its role in colorectal cancer (CRC) with high microsatellite instability (MSI-H) must be further clarified. In our study, we found that GDF15 is generally elevated in pancarcinoma, particularly in colorectal cancer, and serves as an early indicator of the development of colorectal cancer. IHC and WB confirmed that GDF15 was elevated in MSI-H CRC clinical tissues and MSI-H CRC cell lines (HCT-116 and LoVo). Suppressing GDF15 by siRNA resulted in a substantial decrease in cell viability and proliferation. Furthermore, suppressing GDF15 can increase the sensitivity of MSI-H CRC cells to 5-fluorouracil (5-FU), which decreases cell viability and increases the apoptosis rate. In vivo experiments also demonstrated that mouse xenografts with suppressed GDF15 expression were more susceptible to 5-FU chemotherapy. We examined alterations in mitochondria via electron microscopy and changes in the mitochondrial membrane potential, ferroptosis-related signals (MDA, Fe2+), and SLC7A11/GSH/GPX4 protein pathway. Our research indicates that inhibiting GDF15 affects ferroptosis-related pathways, leading to ferroptosis and improving the MSI-H CRC response to 5-FU therapy. As a result, GDF15 could be a promising target for diagnosing and treating MSI-H CRC, potentially enhancing the overall effectiveness of therapy for patients with MSI-H CRC.

Gastric cancer (GC), especially the case with microsatellite stability (MSS) phenotype, has limited efficacy for immune checkpoint blockade (ICB) therapy. Metabolism reprogramming is newly recognized to affect tumor immune microenvironment (TIME). However, the relationship between metabolism reprogramming and immunotherapy for MSS GC has not been reported.

A metabolic stratification for GC was developed based on the glycolysis/cholesterol synthesis axis using the R package "ConsensusClusterPlus". The T cell inflamed score was used to define "immune-hot" and "immune-cold" phenotypes in MSS GC. The anti-tumor and immunological effects of simvastatin were explored using in vitro and in vivo experiments.

Three metabolic subtypes were identified in GC patients, including cholesterol, glycolysis and quiescent subtypes. The cholesterol subtype was associated with poorer clinical features and higher tumor purity. Correspondingly, we demonstrated that simvastatin, a specific inhibitor of cholesterol synthesis, significantly inhibited the proliferation, migration, and induced ferroptosis in GC cells. Interestingly, simvastatin markedly inhibited tumor growth in immunocompetent mice, while no significant effect in immunodeficient mice. Upregulation of chemokines and increased recruitment of CD8+ T cells were observed after simvastatin treatment. Consistently, the cholesterol subtype exhibited a less inflamed TIME and coincided significantly with the "immune-cold" phenotype of MSS GC. Finally, we confirmed simvastatin enhanced PD-1 blockade efficacy via modulating the TIME and activating anti-tumor immunity in tumor-bearing mice.

Our data revealed the significance of cholesterol synthesis in GC and demonstrated simvastatin served as a promising sensitizer for ICB therapy by inducing ferroptosis and anti-tumor immunity in MSS GC patients.

Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells.

Advanced gastroesophageal cancers are still associated with poor outcomes. We aim to study PD-1/PD-L1 inhibitors in phase III clinical trials that have compared them to chemotherapy in gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.

On March 28, 2024, we searched: PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov. We only included randomized clinical trials for PD-1/PD-L1 inhibitors alone or with chemo vs chemotherapy in advanced gastric, GEJ, or esophageal adenocarcinoma. The primary endpoints were overall survival and progression-free survival. A subgroup analysis was conducted for the following variables: treatment line, type of intervention, age group, gender, ECOG Performance Status, combined positive scores (CPS), microsatellite instability (MSI) status, liver metastasis, and primary tumor location.

Only 10 out of 8,942 articles were included, involving 6,782 patients. PD-1/PD-L1 inhibitors showed a significant improvement in the overall survival compared to chemotherapy alone (hazard ratio (HR): 0.86, 95% CI: 0.80-0.93; p = 0.0002). Combining PD-1/PD-L1 inhibitors with chemotherapy significantly improved overall and progression-free survival compared to monotherapy (combined therapy HR 0.80; p < 0.00001 vs. monotherapy HR 0.98; p = 0.77). CPS ≥1 had an HR of 0.78 (95% CI: 0.73-0.84; p < 0.00001), CPS ≥10 had an HR of 0.67 (95% CI: 0.59-0.76; p < 0.00001), and MSI-high status had an HR of 0.35 (95% CI: 0.24-0.52; p < 0.00001). Esophageal adenocarcinoma, reported in three trials, did not show significant improvement in the overall survival (HR 0.89; 95% CI: 0.69-1.14; p = 0.37).

PD-1/PD-L1 inhibitors have significantly improved overall survival, and combining them with chemotherapy is more effective than monotherapy. Both CPS ≥10 and MSI-H showed an added benefit to overall survival and should be included in biomarker investigations. Clinical trials are needed for second-line treatments and esophageal adenocarcinoma.

Gastric cancer (GC) poses a significant health challenge worldwide, necessitating the identification of predictive biomarkers to improve prognosis. Dysregulated lipid metabolism is a well-recognized hallmark of tumorigenesis, prompting investigation into apolipoproteins (APOs). In this study, we focused on apolipoprotein D (APOD) following comprehensive analyses of APOs in pan-cancer. Utilizing data from the TCGA-STAD and GSE62254 cohorts, we elucidated associations between APOD expression and multiple facets of GC, including prognosis, tumor microenvironment (TME), cancer biomarkers, mutations, and immunotherapy response, and identified potential anti-GC drugs. Single-cell analyses and immunohistochemical staining confirmed APOD expression in fibroblasts within the GC microenvironment. Additionally, we independently validated the prognostic significance of APOD in the ZN-GC cohort. Our comprehensive analyses revealed that high APOD expression in GC patients was notably associated with unfavorable clinical outcomes, reduced microsatellite instability and tumor mutation burden, alterations in the TME, and diminished response to immunotherapy. These findings provide valuable insights into the potential prognostic and therapeutic implications of APOD in GC.

Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R2 = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC.

Microsatellite instable (MSI) gastric cancers exhibit reduced lymph node (LN) metastasis and improved survival compared to microsatellite stable (MSS) counterparts. However, to our longstanding observation, clinical N-staging (cN) is frequently overestimated in MSI cases. The clinical implications and underlying mechanisms of this discrepancy warrant further investigation.

We conducted a comprehensive review of clinicopathological data from a 141 MSI and 1119 MSS gastric cancer patients. Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were assessed using qPCR and immunohistochemistry. High-parameter flow cytometry was employed to analyze subsets of CD8+ T cells within the tumors.

Multivariate analysis revealed that MSI status was an independent prognostic factor, alongside the LN ratio and AJCC8 pathology staging. MSI gastric cancers exhibited a reduced LN ratio, particularly at advanced T-staging, compared to MSS counterparts, while maintaining an equivalent LN yield. Overestimation of cN by computed tomography preoperatively was frequent in MSI gastric cancers but was more commonly underestimated in MSS counterparts. VEGF-C and VEGFR-3 expression were lower in MSI tumors. MSI gastric cancers showed an increased total number of CD8+ T cells, albeit with a lower proportion of effector memory cells expressing CD45RA (EMRA) and CD8+ CXCR4+ T cells, compared to MSS counterparts.

Frequent overestimation of clinical N-staging in MSI gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics and should be cautiously interpreted, as it might misguide therapeutic options.

Targeting cancer-specific vulnerabilities through synthetic lethality (SL) is an emerging paradigm in precision oncology. A SL strategy based on PARP inhibitors has demonstrated clinical efficacy. Advances in DNA damage response (DDR) uncover novel SL gene pairs. Beyond BRCA-PARP, emerging SL targets like ATR, ATM, DNA-PK, CHK1, WEE1, CDK12, RAD51, and RAD52 show clinical promise. Selective and bioavailable small molecule inhibitors have been developed to induce SL, but optimization for potency, specificity, and drug-like properties remains challenging. This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.

High expression of programmed death-ligand 1 (PD-L1) has been recognized as a marker of improved efficacy of immunotherapy in gastroesophageal adenocarcinoma (GEA); however, the optimal PD-L1 cut-off is still debated. The aim of the present review was to analyze available phase III trials and to identify the appropriate PD-L1 expression cut-off for GEA.

Phase III trials investigating the efficacy of anti-programmed cell death protein 1 (PD-1) therapies in addition to standard chemotherapy versus standard chemotherapy in the first-line setting were selected. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were the analyzed outcome measures. Pooled treatment effects were assessed in the unselected population and in subpopulations with different levels of PD-L1 expression.

PD-1 blockade efficacy was found to consistently increase in a linear manner with higher combined positive score (CPS) of PD-L1 expression: pooled hazard ratio (HR) for OS and PFS and pooled odds ratio (OR) for ORR of 0.80, 0.75 and 1.51, respectively, in the unselected population versus 0.67, 0.63 and 1.90, respectively, in the CPS ≥10 population (all P values < 0.0001). In the PD-L1-negative population (CPS <1) a significant benefit of anti-PD-1 agents could not be demonstrated in terms of OS and PFS (P = 0.28 and 0.12, respectively), but it was seen in terms of ORR (P = 0.03). PD-1 blockade was effective in the CPS <10 population (P value for pooled OS HR, PFS HR and response OR are all 0.01), while in the CPS <5 population the effect was of borderline significance for OS (P = 0.07) and significant for PFS and ORR (P = 0.02 and 0.03, respectively).

The present meta-analysis confirmed that the benefit of PD-1 blockade in GEA patients is related to PD-L1 CPS, with increased benefit observed for higher CPS cut-offs and no OS benefit in the CPS <1 subset. Overall, data indicate that PD-L1 CPS ≥5 could represent an acceptable cut-off to optimize the risk/benefit ratio of such agents. Our data suggest a potential clinical benefit of immunotherapy in selected patients within the CPS 1-4 population which needs further investigation.

Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.

Early screening is crucial for the prevention of intestinal-type gastric cancer. The objective of the current study was to ascertain molecular evolution of intestinal-type gastric cancer according to the Correa cascade for the precise gastric cancer screening. We collected sequential lesions of the Correa cascade in the formalin-fixed and paraffin-embedded endoscopic submucosal dissection-resected specimens from 14 Chinese patients by microdissection, and subsequently determined the profiles of somatic aberrations during gastric carcinogenesis using the whole exome sequencing, identifying multiple variants at different Correa stages. The results showed that TP53, PCLO, and PRKDC were the most frequently mutated genes in the early gastric cancer (EGC). A high frequency of TP53 alterations was found in low-grade intraepithelial neoplasia (LGIN), which further increased in high-grade intraepithelial neoplasia (HGIN) and EGC. Intestinal metaplasia (IM) had no significant correlation with EGC in terms of mutational spectra, whereas both LGIN and HGIN showed higher genomic similarities to EGC, compared with IM. Based on Jaccard similarity coefficients, three evolutionary models were further constructed, and most patients showed linear progression from LGIN to HGIN, ultimately resulting in EGC. The ECM-receptor interaction pathway was revealed to be involved in the linear evolution. Additionally, the retrospective validation study of 39 patients diagnosed with LGIN indicated that PRKDC mutations, in addition to TP53 mutations, may drive LGIN progression to HGIN or EGC. In conclusion, the current study unveils the genomic evolution across the Correa cascade of intestinal-type gastric cancer, elucidates the underlying molecular mechanisms of gastric carcinogenesis, and provides some evidence for potential personalized gastric cancer surveillance.

Circular RNA (circRNA) is a unique type of noncoding RNA molecule characterized by its closed-loop structure. Functionally versatile, circRNAs play pivotal roles in gene expression regulation, protein activity modulation, and participation in cell signaling processes. In the context of cancers of the digestive system, the Wnt signaling pathway holds particular significance. Anomalous activation of the Wnt pathway serves as a primary catalyst for the development of colorectal cancer. Extensive research underscores the notable participation of circRNAs associated with the Wnt pathway in the progression of digestive system tumors. These circRNAs exhibit pronounced dysregulation across esophageal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma. Furthermore, the altered expression of circRNAs linked to the Wnt pathway correlates with prognostic factors in digestive system tumors. Additionally, circRNAs related to the Wnt pathway showcase potential as diagnostic, therapeutic, and prognostic markers within the realm of digestive system tumors. This comprehensive review outlines the interplay between circRNAs and the Wnt signaling pathway in cancers of the digestive system. It seeks to provide a comprehensive perspective on their association while delving into ongoing research that explores the clinical applications of circRNAs associated with the Wnt pathway.

In gastric cancer, gastrokine 1 (GKN1) is a potential theragnostic marker while the related mechanisms remain elusive. Exosomes mediate intercellular communications via transferring various molecules, yet there are limited research studies on the specific cargos of gastric cancer exosomes and the associated mechanisms in this disease. In the present study, AGS and N87-C cells were transfected with an overexpressed GKN1 plasmid, followed by extraction of exosomes. The study utilized gastric cancer cell lines and a xenograft mouse model to investigate the functional significance of exosomal GKN1. Cell proliferation, metastasis, and apoptosis were assessed through CCK-8, Transwell, and flow cytometry assays, respectively. The study further explored the mechanism of exosomal GKN1 and its interaction with the PI3K/AKT/mTOR signaling pathways, including immunofluorescence and western blot analyses. Exosomal GKN1 was observed to suppress cell proliferation and invasion while enhancing apoptosis. This effect was attributed to the modulation of key proteins involved in cellular processes, including Ki-67, MMP-9, Bcl-2, Bax, caspase-3, and caspase-9, ultimately impacting the PI3K/AKT/mTOR signaling pathway. The findings suggest that exosomal GKN1 exerts inhibitory effects on gastric cancer cell growth and invasion through the regulation of the PI3K/AKT/mTOR signaling cascade, both in experimental cell cultures and animal models.

Microsatellite instability (MSI) has been widely acknowledged as an important factor regulating tumor intrinsic biological behavior and affecting the survival of gastric cancer patients. Here, we firstly identified the RARB as a gene associated with MSI gastric cancer. RARB was downregulated in human gastric cancer tissues compared to paired paracancerous tissues, Knockdown of RARB accelerated the proliferation, invasion and migration of cancer cells in vitro. Mechanismly, RARB knockdown promoted epithelial-mesenchymal transition (EMT) process of gastric cancer. However, RARBLow patients exhibited better survival compared to RARBHigh patients. Further study revealed that RARB expression was inversely correlated with MSI status and immune infiltrates in vivo. Thus, RARB may be a potential target for the treatment of gastric cancer.

The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.

We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ).

This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue.

Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations.