Signet ring cell carcinoma (SRCC) poses a considerable challenge in terms of treatment, given its refractory nature and poor outcomes. Unlike other cancers, SRCC exhibits significant MDM2 copy number gains, with elevated MDM2 expression linked to poor prognosis. MDM2 inhibition induces a morphological transition in SRCC cells by suppressing E-cadherin degradation, which may render these cells vulnerable to a second drug. Using a high-throughput drug screen, our study demonstrated that the combination of MDM2 inhibitors with G2/M checkpoint inhibitors, including WEE1 or CHK1 inhibitors, can elicit a synergistic antitumor response in SRCC cells by inducing DNA damage. Furthermore, pharmacological inhibition of MDM2, WEE1, or CHK1 significantly impeded tumor growth in in vivo mouse models and organoids of SRCC. Collectively, our findings indicate that MDM2 inhibition-induced morphological changes may enhance the efficacy of G2/M checkpoint inhibitors, presenting a promising combined treatment for SRCC.

In recent years, the global prevalence of gastric cancer (GC) has witnessed a progressive decrease, accompanied by a step-growth in the incidence of gastric signet ring cell carcinoma (GSRCC). As precision medicine concepts progress, GSRCC, a distinct sub-type of GC, has drawn considerable attention from researchers. However, there still persist some controversies regarding the associated research findings.

To summarize the current obstacles and potential future directions for research on GSRCC.

To begin with, all literature related to GSRCC published from January 1, 2004 to December 31, 2023 was subjected to bibliometric analysis in this article. Additionally, this paper analyzed the research data using CiteSpace, GraphPad Prism v8.0.2, and VOSviewer, which was obtained from the Web of Science Core Collection database. The analysis results were visually represented.

This study provided a comprehensive overview of the statistical characteristics of the 995 English articles related to GSRCC, including cited references, authors, journals, countries, institutions, and keywords. The popular keywords and clusters contain "prognosis", "survival", "expression", "histology", and "chemotherapy".

The prognosis, precise definition and classification, as well as chemoresistance of GSRCC, continue to be crucial areas of ongoing research, whose directions are closely tied to advancements in molecular biology research on GSRCC.

Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer; however, its clinical relevance in the context of immune checkpoint inhibitor-based chemotherapy is not known. This study aimed to investigate the efficacy of nivolumab plus chemotherapy according to claudin 18.2 expression in patients with gastric cancer.

This single-center study included patients with advanced gastric cancer who were treated with first-line nivolumab plus chemotherapy (n = 204) or chemotherapy alone (n = 183) whose claudin 18.2 immunohistochemistry results were available. Claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was analyzed in terms of efficacy outcomes.

Among patients treated with nivolumab plus chemotherapy, 96 (47.1%) were assessed to have claudin 18.2-positive tumors. Between patients with claudin 18.2-positive and -negative tumors, objective response rate with nivolumab plus chemotherapy was comparable. Progression-free survival (PFS) and overall survival (OS) with nivolumab plus chemotherapy were comparable between those with claudin 18.2-positive and -negative tumors. For both subgroups with PD-L1 combined positive score ≥ 5 and < 5, PFS and OS with nivolumab plus chemotherapy were also comparable between patients with claudin 18.2-positive and -negative tumors. A consistent trend of favorable PFS and OS was observed with nivolumab plus chemotherapy compared to that of chemotherapy alone in both claudin 18.2-positive and -negative subgroups.

The efficacy of nivolumab plus chemotherapy did not vary according to claudin 18.2 positivity. The clinical benefit of nivolumab plus chemotherapy over chemotherapy was consistently observed in claudin 18.2-positive and -negative gastric cancer cases.

Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficult isolation of neoantigen-specific T cells limits the clinical application of ACT. Here, we propose a method to prepare neoantigen-reactive T cells (NRT) for ACT following immunization with a tumor lysate-loaded dendritic cell (DC) vaccine. We show that the DC vaccine not only induces a neoantigen-reactive immune response in lung cancer-bearing mice in vivo, but also facilitate NRT cell preparation in vitro. Adoptive transfer of the NRTs as combinatorial therapy into DC vaccine-immunized, LL/2 tumor-bearing mice allows infiltration of the infused NRTs, as well as the enrichment of neoantigen reactive, non-ACT/NRT T cells into the tumor microenvironment with the function of these neoantigen-reactive T-cell receptors validated in vitro. In summary, we propose a method for preparing NRTs that increases ACT efficacy and paves the way to the design of personalized immunotherapies.

Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several preanalytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation; thus, this article provides practical guidance on CLDN18.2 testing and scoring in gastric and gastroesophageal junction adenocarcinomas to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cutoff for clinical use of monoclonal antibody anti-CLDN18.2 (zolbetuximab).

Poor prognosis in patients with distant metastasis of gastric signet ring cell carcinoma (GSRC), and there are few studies on the development and validation of the diagnosis and prognosis of distant metastasis of GSRC. The Surveillance, Epidemiology, and End Results database was used to identify patients with GSRC from 2004 to 2019. Univariate and multivariate logistic regression analysis were used to identify independent risk factors for distant metastasis of GSRC, while univariate and multivariate Cox proportional hazard regression analysis were used to determine independent prognostic factors for patients with distant metastasis of GSRC. Two nomograms were established, and model performance was evaluated using receiver operating characteristic curves, calibration plots, and decision curve analysis. A total of 9703 cases with GSRC were enrolled, among which 2307 cases (23.78%) were diagnosed with distant metastasis at the time of diagnosis. Independent risk factors for distant metastasis included age, race, and T stage. Independent prognostic factors included T stage, chemotherapy, and surgery. The receiver operating characteristic curve, calibration curve, decision curve analysis curve, and Kaplan-Meier survival curve of the training set and validation set confirmed that the 2 nomograms could accurately predict the occurrence and prognosis of distant metastasis in GSRC. Two nomograms can serve as effective prediction tools for predicting distant metastasis in GSRC patients and the prognosis of patients with distant metastasis. They have a certain clinical reference value.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.

Gastric signet-ring cell carcinoma (GSRCC) is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis. Studies have shown that early GSRCC has a good prognosis, while advanced GSRCC is insensitive to radiotherapy, chemotherapy or immune checkpoint blockade therapy. With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry, more detailed atlas of tumor microenvironment (TME) in GSRCC and its association with prognosis could be investigated extensively. Recently, two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME, manifested as highly immunosuppressive, leading to high immune escape. The TME of advanced GSRCC was enriched for immunosuppressive factors, including the loss of CXCL13 +-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells. In addition, GSRCC was mainly infiltrated by follicular B cells. The increased proportion of SRCC was accompanied by a decrease in mucosa-associated lymphoid tissue-derived B cells and a significant increase in follicular B cells, which may be one of the reasons for the poor prognosis of GSRCC. By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism, more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.

The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.

CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.

Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations.

We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC.

We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth.

These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.

Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear.

We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay.

RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle-lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle-lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12-7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named "microtubular-mucocellular (MTMC) histology," was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%).

RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.

Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.

Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.

Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC.

Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms. This review aims to explore these complexities, offering insights into the optimal sequencing of chemotherapy and targeted therapies and their utility in the management of GE and PB cancers. The timely integration of promising investigational therapies into clinical practice has broader implications around strategies for future clinical trial designs, which would pave the way for advancements in the management of GE and PB cancers. This review provides guidance in navigating the evolving landscape of GE and PB cancer care, which ultimately will drive forward progress in the field and lead to improved patient outcomes.

Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.

Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe.

Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry.

Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available.

Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

The objective of our study was to develop a nomogram to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric signet ring cell carcinoma (GSRCC).

A total of 3,408 GSRCC patients between 1975 and 2017 were screened from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training and validation cohorts. Univariate and multivariate Cox analyses were conducted to identify independent prognostic factors for the construction of a nomogram. The performance of the model was then assessed by the concordance index (C-index), calibration plot, and area under the receiver operating characteristic curve (AUC). Then, the novel nomogram was further assessed by 64 GSRCC patients from our hospital as the external cohort.

We identified age, tumor lymph node metastasis (TNM) staging system, surgery, and chemotherapy as significant independent elements of prognosis. On this basis, a nomogram was constructed, with a C-index of OS in the training and validation cohorts of 0.763 (95% CI: 0.751-0.774) and 0.766 (95% CI: 0.748-0.784) and a C-index of CSS of 0.765 (95% CI: 0.753-0.777) and 0.773 (95% CI: 0.755-0.791), respectively. The AUCs of the nomogram for predicting 2- and 5-year OS were 0.848 and 0.885, respectively, and those for predicting CSS were 0.854 and 0.899, respectively, demonstrating the excellent predictive value of the constructed nomogram compared to the traditional AJCC staging system. Similar results were also observed in both the internal and external validation sets.

The nomogram provided an accurate tool to predict OS and CSS in patients with GSRCC, which can assist clinicians in making predictions about individual patient survival.

Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.

Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.

Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.

Globally, gastrointestinal cancer is the most widespread neoplastic disease and the primary contributor to cancer-associated fatalities. Gastrointestinal signet ring cell carcinoma (SRCC) exhibits unique distinguishing features in several aspects when compared to adenocarcinomas (ACs). The scarcity of signet ring cell carcinoma has resulted in a heightened significance of related clinical and molecular investigations. However, a comprehensive and systematic review of the clinical, molecular, therapeutic, and research aspects of this disease is currently absent. This review provides an overview of the latest developments in our understanding of the clinical and molecular features of gastrointestinal signet ring cell carcinoma (SRCC). Additionally, we have compiled a list of potential therapeutic targets or biomarkers, as well as an examination of the current treatment options and the possible mechanisms of formation.

Claudins are four-transmembrane proteins, which were found in tight junctions. They maintain cell barriers and regulate cell differentiation and proliferation. They are involved in maintaining cellular polarity and normal functions. Different claudins show different expression patterns. The expression level and localization of claudins are altered in various cancers. They promote or inhibit proliferation, invasion, and migration of cancer cells through multiple signaling pathways. Therefore, claudins may serve as diagnostic markers, novel therapeutic targets, and prognostic risk factors. The important roles of claudins in cancer aroused our great interest. In the present review, we provide a summary of insights into expression patterns of claudins in cancer, which is more comprehensive and provides new ideas for further research.

To evaluate cancer-specific survival (CSS) and construct a nomogram to predict the CSS of patients with colorectal signet ring cell carcinoma (SRCC).

The data for patients with colorectal SRCC from 2000 to 2019 was identified from Surveillance, Epidemiology, and End Results (SEER) database. Propensity Score Matching (PSM) was used to minimize bias between SRCC and adenocarcinoma patients. Kaplan-Meier method and log-rank test were used to estimate the CSS. A nomogram was constructed based on the independent prognostic factors identified by univariate and multivariate Cox proportional hazards regression analyses. The model was evaluated by receiver operating characteristic (ROC) curves and calibration plots.

Poor CSS was more common in patients with colorectal SRCC, especially in patients with T4/N2 stage, tumor size > 80 mm, grade III-IV, and chemotherapy. Age, T/N stage, and tumor size > 80 mm were identified as independent prognostic indicators. And a prognostic nomogram was constructed and validated as an accurate model for the CSS of patients with colorectal SRCC by ROC curves and calibration plots.

Patients with colorectal SRCC have a poor prognosis. And the nomogram was expected to be effective in predicting the survival of patients with colorectal SRCC.

Claudin18.2 (Cldn18.2) is a tight junction protein expressed in gastric epithelial cells and is an emerging target for gastric cancer (GC). This study aimed to analyze the correlation between Cldn18.2 and clinicopathological parameters in GC patients undergoing radical surgery.

This study included 426 GC patients who underwent radical gastrectomy. The expression of Cldn18.2 was analyzed by immunohistochemical staining and grading. The statistical results indicated that the expression of Cldn18.2 was correlated with T stage, TNM stage, Lauren classification, and the expression level of Mucin-2 (MUC2), Mucin-5AC (MUC5AC), Mucin-6 (MUC6), human epidermal growth factor receptor 2 (HER2), P53 and trefoil factor 2 (TFF2). In addition, through data mining of the Cancer Genome Atlas (TCGA) database, it is suggested that Cldn18.2 expression level is significantly correlated with the expression level of MUC5AC, MUC6, and TFF2. Besides, Cldn18.2 is related to tumor immune infiltration, programmed cell death protein 1 (PD 1) pathway, cell cycle and Wnt signaling pathway.

The expression of Cldn18.2 was closely related to gastric-type GC, so gastric-type GC patients may benefit more from targeted drugs targeting Cldn18.2. In GC cells, depletion of Cldn18.2 may influence cell cycle and immune response by affecting Wnt signaling pathway and PD 1 pathway.

Gastric cancer is a prevalent malignancy with a high degree of heterogeneity, which has led to a poor therapeutic response. Though there are numerous HER2-targeted medicines for HER2+ gastric cancer, many trials have not indicated an improvement in overall survival. Here 29 ERBB2 amplification (ERBB2-Amp) type gastric cancer samples with WES and RNA-seq data were selected for investigation, which copy-number aberration (CNA) was +2. Initially, the somatic mutation and copy number variant (CNV) of them, which might cause resistance to HER2-targeted therapies, were systematically investigated evaluated, as well as their mutation signatures. Moreover, 37 modules were identified using weighted gene co-expression network analysis (WGCNA), including the blue module related to DFS status and lightcyan module correlated with ARHGAP26_ARHGAP6_CLDN18 rearrangement. In addition, focal adhesion and ECM-receptor interaction pathways were considerably enriched in the turquoise module with ERBB2 gene. ExportNetworkToCytoscape determined that MIEN1 and GRB7 are tightly connected to ERBB2., Finally, 14 single-cell intestinal gastric cancer samples were investigated, and it was shown that the TFAP2A transcription factor regulon was highly expressed in ERBB2high group, as was the EMT score. Overall, our data provide comprehensive molecular characteristics of ERBB2-Amp type gastric cancer, which offers additional information to improve HER2-targeted gastric cancer treatment.

Signet ring cell carcinoma accounts for 35% to 45% of all gastric cancer. Despite the acknowledgment of its more aggressive pathological features, various controversies surrounding this topic still exist. Thus, we investigate the clinical pathological characteristics and survival prognostic significance of signet ring cell components in patients affected by gastric cancer.

From January 2004 to December 2020, in a retrospective study, we enrolled 404 patients with gastric cancer who were curatively treated in our department. The male-to-female ratio was 249/142, and the median age was 75 (range 37-94). We dichotomized patients into two groups (75 patients vs. 316 patients) based on the signet ring cell presence; according to preoperative, operative, and postoperative characteristics, we performed a univariate and multivariate analysis for overall survival.

Signet ring cell carcinoma indicated an increasing incidence trend over the time analyzed. Overall median survival of signet ring cell and non-signet ring cell carcinoma were, respectively, 16 vs. 35 months, p < 0.05. In early gastric cancer, the prognosis of the signet ring cell is better than that of the non-signet ring cell, as opposed to advanced cancer. Among the entire population in the multivariate analysis, the only independent factors were preoperative serum albumin level, complete surgical resection, level of lymphadenectomy, and pathological stage. Recurrence occurred more frequently in patients affected by signet ring cell, but in our data, we could not identify a peculiar site of recurrence.

Signet ring cell carcinoma has a specific oncogenetic phenotype and treatment resistance heterogeneity; however, it is not always associated with poor prognosis. According to our results, a radical surgical procedure associated with an adequate lymphadenectomy should be advocated to improve patients survival. Gastric cancer patients with signet ring cell components should draw clinicians' attention.

Gastric signet ring cell carcinoma (GSRC) is a special subtype of gastric cancer (GC) associated with poor prognosis, but an in-depth and systematic study of GSRC is lacking. Here, we perform single-cell RNA sequencing to assess GC samples. We identify signet ring cell carcinoma (SRCC) cells. Microseminoprotein-beta (MSMB) can be used as a marker gene to guide the identification of moderately/poorly differentiated adenocarcinoma and signet ring cell carcinoma (SRCC). The upregulated differentially expressed genes in SRCC cells are mainly enriched in abnormally activated cancer-related signalling pathways and immune response signalling pathways. SRCC cells are also significantly enriched in mitogen-activated protein kinase and oestrogen signalling pathways, which can interact and promote each other in a positive feedback loop. SRCC cells are shown to have lower cell adhesion and higher immune evasion capabilities as well as an immunosuppressive microenvironment, which may be closely associated with the relatively poor prognosis of GSRC. In summary, GSRC exhibits unique cytological characteristics and a unique immune microenvironment, which may be advantageous for accurate diagnosis and treatment.

Gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with a poor prognosis. Chemotherapy has been the cornerstone in treating metastatic diseases. Recently, the introduction of immunotherapy demonstrated improved survival outcomes in localized and metastatic diseases. Beyond immunotherapy, several attempts were made to improve patient survival by understanding the molecular mechanisms of GEA and several molecular classifications were published. In this narrative review, we will discuss emerging targets in GEA, including fibroblast growth factor receptor and Claudin 18.2, as well as the accompanying drugs. In addition, novel agents directed against well-known targets, such as HER2 and angiogenesis, will be discussed, as well as cellular therapies like CAR-T and SPEAR-T cells.

The tumor, nodes, metastasis (TNM) staging system has long been the gold standard for the classification and prognosis of solid tumors. However, the TNM staging system is not without limitations. Prognostic heterogeneity exists within patients at the same stage. Therefore, the pursuit of other biomarkers with the potential to classify patients with cancer has never stopped. One of them, tumor budding (TB), has gained much success in colorectal cancer. In recent years, TB in gastric cancer has attracted much attention from researchers, beginning to reveal the molecular and biological aspects of this phenomenon in gastric cancer, and has emerged as a promising prognostic biomarker in gastric cancer, predicting disease progression and unfavorable survival. Therefore, it is time and essential to provide a holistic overview of TB in gastric cancer, which has not been achieved and is the aim of this review.

Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor and immune dysfunction is associated with ccRCC poor prognosis. The RhoGTPase-activating proteins (RhoGAPs) family was reported to affect ccRCC development, but its role in immunity and prognosis prediction for ccRCC remain unknown. In the current study, we found ARHGAP11A was the only independent risk factor among 33 RhoGAPs (hazard ratio [HR] 1.949, 95% confidence interval [CI] 1.364-2.785). High ARHGAP11A level was associated with shorter overall survival (OS, HR 2.040, 95% CI 1.646-3.417) and ARHGAP11A is a prognostic biomarker for ccRCC. ARHGAP11A knockdown suppressed renal cell carcinoma (RCC) cell proliferation, colony formation, and migration, suggesting the promoting role of ARHGAP11A on RCC development. Mechanistically, ARHGAP11A might contribute to the suppressive tumor immune microenvironment (TIME). High ARHGAP11A level was correlated with infiltration of immunosuppressive cells (including T helper 2 (Th2) cells, regulatory T (Treg) cells, myeloid derived suppressor cells (MDSC), and M2 macrophage cells), activation of immunosuppressive pathways (IL6-JAK-STAT3 signaling and IFNγ response), and expression of inhibitory immune checkpoints (ICs). ARHGAP11A could promote T cell exhaustion and induce immune escape. ccRCC patients with low ARHGAP11A level were more suitable for immune checkpoint inhibitors (ICIs) therapy, while those with high ARHGAP11A level might benefit from a combination of ARHGAP11A blockade and ICIs. In all, ARHGAP11A might serve as a novel prognostic marker, therapeutic target, and predictor in the clinical response to ICIs therapy for ccRCC.

Adenocarcinoma of the esophagus (EAC) and gastroesophageal junction (GEJ-AC) is associated with poor prognosis, treatment resistance and limited systemic therapeutic options. To deeply understand the genomic landscape of this cancer type, and potentially identify a therapeutic target in a neoadjuvant chemotherapy non-responder 48-year-old man, we adopted a multi-omic approach. We simultaneously evaluated gene rearrangements, mutations, copy number status, microsatellite instability and tumor mutation burden. The patient displayed pathogenic mutations of the TP53 and ATM genes and variants of uncertain significance of three kinases genes (ERBB3, CSNK1A1 and RPS6KB2), along with FGFR2 and KRAS high copy number amplification. Interestingly, transcriptomic analysis revealed the Musashi-2 (MSI2)-C17orf64 fusion that has never been reported before. Rearrangements of the RNA-binding protein MSI2 with a number of partner genes have been described across solid and hematological tumors. MSI2 regulates several biological processes involved in cancer initiation, development and resistance to treatment, and deserves further investigation as a potential therapeutic target. In conclusion, our extensive genomic characterization of a gastroesophageal tumor refractory to all therapeutic approaches led to the discovery of the MSI2-C17orf64 fusion. The results underlie the importance of deep molecular analyses enabling the identification of novel patient-specific markers to be monitored during therapy or even targeted at disease evolution.

The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and β-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of β-catenin and strongly influences the chemosensitivity of BC cells.

Metastasis is the leading cause of treatment failure and tumor-related death in colorectal cancer (CRC). Our previous studies report that CEMIP functionally promotes CRC metastasis and is closely related to poor outcomes. However, the molecular network of CEMIP promoting CRC metastasis is still not fully understood. In the current study, we identify CEMIP interacting with GRAF1, and the combination of high-CEMIP and low-GRAF1 predicts poor survival of patients. Mechanistically, we elucidate that CEMIP interacts with the SH3 domain of GRAF1 through the 295-819aa domain, and negatively regulates the stability of GRAF1. Moreover, we identify MIB1 to be an E3 ubiquitin ligase for GRAF1. Importantly, we uncover that CEMIP acts as a scaffold protein in bridging MIB1 and GRAF1, which is critical to GRAF1 degradation and CEMIP-mediated CRC metastasis. Furthermore, we found that CEMIP activates CDC42/MAPK pathway-regulated EMT by enhancing the degradation of GRAF1, which is indispensable to CEMIP-mediated migration and invasion of CRC cells. Subsequently, we prove that CDC42 inhibitor suppresses CEMIP-mediated CRC metastasis in vitro and in vivo. Collectively, our results reveal that CEMIP promotes CRC metastasis through GRAF1/CDC42/MAPK pathway-regulated EMT, and suggest that CDC42 inhibitor could be a novel therapeutic strategy for CEMIP-mediated CRC metastasis.

We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC).

Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression.

Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status.

CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC.

To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole-exome sequencing (WES) was performed on a 58-year-old male patient who had painless macroscopic hematuria and was pathologically diagnosed with primary SRCC of the bladder, followed by comparing with genes of ordinary urothelial cancer (UC) from TCGA. Furthermore, a population-based analysis using the SEER database was performed to investigate the prognosis (SRCC vs. UC). We identified 63 copy number variations (CNVs) with gain counts and 181 CNVs with loss counts. Totally 4515 mutations were discovered in C > T with a success rate of greater than 89%. The most frequently mutated pathway was RTK-RAS which has 85 genes involved in carcinogenic signaling. Final screening on predisposing genes is performed after filtering based on ACMG. Moreover, several driver genes, including NBN, KCTD18, SPATA13, ANKRD36, OR2L5, MALRD1, and LSMEM1, were detected. Sanger sequencing of germline DNA revealed the presence of a mutant base A/G of OR2L5 in the sequence, which was discovered for the first time in primary SRCC of the bladder. Furthermore, the immunohistochemical profile showed that primary SRCC of the bladder were positive for CK7, CK20, GATA-3, and expression of CK(AE1/AE2), EMA, and Ki67. In the SEER-based study, the patients with primary SRCC of the bladder got a worse prognosis compared to those with UC with median months overall survival (OS) 14 vs. 41, respectively, P = 0001, even after adjusting the variables in the Cox regression model, the SRCC of the bladder showed worse survival HR = 1.119, 95% CI = (1.081-1.328), P = 0.0001. These results imply that suppression of potential driver mutations may be a viable adjuvant treatment approach for primary SRCC in the bladder in place of standard chemotherapy, a possibility that warrants further clinical investigation.

Signet ring cell carcinoma (SRCC) is a specific type of gastric cancer. The clinicopathological and molecular characteristics that can be used to predict the response to anti-PD-1 therapy for these patients are still not clear.

Patients with advanced SRCC who received first-line anti-PD-1-based treatment were enrolled in this study. The clinicopathological characteristics of these patients were obtained from their medical records. The molecular features of these patients were analyzed by means of a next-generation-sequencing-based panel. The predictive significance of clinicopathological and molecular features for efficacy was analyzed.

A total of 71 patients with measurable lesions were included in this study, among which 46 patients had enough tissues for next-generation sequencing. The overall objective response rate (ORR) was 46.4%. ORR was significantly higher in mismatch repair (MMR)-deficient (dMMR) patients than in MMR-proficient (pMMR) patients, in patients with lymph node metastasis only than those with other metastasis sites, and in patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 than with a PS of 1 or 2. The progression-free survival was significantly longer in patients with dMMR, lymph node metastasis only, PD-L1 combined positive score (CPS) ≥ 5, and CDH1 wild type.

Several clinicopathological and molecular features are associated with anti-PD-1 treatment efficacy in SRCC, which might be used to identify patients who can benefit most from these therapies.