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Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC. [ABSTRACT FROM AUTHOR]

Background: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and is a major cause of mortality. Risk stratification for PM can optimize decision making in GC treatment. Methods: A total of 25 GC patients (13 with synchronous, 6 with metachronous PM and 6 PM-free) were included in this study. Quantitative proteomics by high-depth tandem mass tags labeling and whole-exome sequencing were conducted in primary GC and PM samples. Proteomic signature and prognostic model were established by machine learning algorithms in PM and PM-free GC, then validated in two external cohorts. Tumor-infiltrating immune cells in GC were analyzed by CIBERSORT. Results: Heterogeneity between paired primary and PM samples was observed at both genomic and proteomic levels. Compared to primary GC, proteome of PM samples was enriched in RNA binding and extracellular exosomes. 641 differently expressed proteins (DEPs) between primary GC of PM group and PM-free group were screened, which were enriched in extracellular exosome and cell adhesion pathways. Subsequently, a ten-protein signature was derived based on DEPs by machine learning. This signature was significantly associated with patient prognosis in internal cohort and two external proteomic datasets of diffuse and mixed type GC. Tumor-infiltrating immune cell analysis showed that the signature was associated with immune microenvironment of GC. Conclusions: We characterized proteomic features that were informative for PM progression of GC. A protein signature associated with immune microenvironment and patient outcome was derived, and it could guide risk stratification and individualized treatment. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine. Methods: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis. Results: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis. Conclusions: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease. Alpha-fetoprotein producing gastric carcinomas (AFPGC) are rare and aggressive. Here, the authors profile AFPGC tumours using whole exome sequencing, and find amplifications in CCNE1 and ERBB2 that are associated with poor outcomes but are potential therapeutic targets, as shown in patient-derived xenografts. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) remains a refractory cancer particularly in Eastern Asia. Large tumor suppressor kinases 1/2 (LATS1/2) are core members of the Hippo pathway. The role of LATS1/2 in the prognosis of different subtypes of advanced gastric cancer and its relationship with the tumor immune microenvironment in GC remain unknown. Exploring the role of LATS1/2 in GC might provide potential immunotherapeutic approaches for treating GC. Methods: Four hundred and ninety surgically resected primary GC samples were assessed for LATS1/2, CD8, FOXP3, and CD163. Correlations between LATS1/2 expression and immune-related markers were investigated and the prognoses of patients with different GC subtypes were analyzed. Results: CD8 and CD163 appeared to be favorable and adverse prognostic factors, respectively. LATS1/2 and FOXP3 did not predict patients' overall survival. However, in microsatellite-stable GC patients, high LATS1/2 and FOXP3 expression and low CD8 expression predicted poor prognoses. Furthermore, high LATS1/2 expression was significantly correlated with decreased CD8 and increased FOXP3. Combined analysis of LATS1/2, CD8, and FOXP3 had better prognostic accuracy than did each marker individually. Conclusions: Different biological molecules can predict the prognoses of different types of GC patients. LATS1/2, core kinases in the Hippo pathway, are closely related to CD8 and FOXP3. Further understanding the mechanisms of LATS1/2 in CD8+ T cells and FOXP3+ Treg cells provides further theoretical basis and potential targets for GC immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients.Methods: We analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes.Results: In total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005).Conclusions: Dynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients. [ABSTRACT FROM AUTHOR]

The rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2 (mTORC2), maintains the integrity of the complex and functions as regulator of Akt full activation. Rictor has been implicated to be involved in growth and progression of malignancies, however, little is known about its expression and prognostic role in gastric cancer in particular. Therefore, we investigated the relationship of Rictor expression with clinical outcomes, together with pAktSer473 and pS6, two downstream substrates of mTORC2 and mTORC1, in 396 gastric cancer tissue samples via immunohistochemistry. The results showed that 74.0% and 55.8% of tumors were Rictor and pAktSer473 positive staining, respectively, which correlated well with each other. Patients with positive expressions had poorer overall survival and relapse-free survival compared with those negative staining. Both Rictor and pAktSer473 expression were associated with lymph node metastasis, TNM stage, and WHO grading. Rictor was also correlated with tumor size, depth of invasion, and tumor thrombus, while pAktSer473 was also correlated with distant metastasis. In spite of 67.4% expression rate was presented in gastric cancer tissues, no significant association was observed between pS6Ser235/236, representing mTORC1 activity, and clinicopathological features or prognosis. These results suggest that mTORC2/Rictor/pAkt may play a more important role than mTORC1/pS6 in tumor progression, which could act as a prognostic biomarker or potential therapeutic target in gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric Cancer (GC) is the fifth leading cause of cancer-related death in the world, and in urgent need of specific therapeutic targets to acquire prominent effectiveness. T-cell immunoglobulin and immunoreceptor tyrosine–based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are identified to be abnormally overexpressed in various types of cancers including GC. This study aimed to investigate whether TIGIT and PD-1 could serve as potential prognostic biomarkers for GC. Firstly, TCGA GC dataset analysis and correlation analysis were utilized to inspect the relationship between expression of TIGIT, PD-1 and CD8 + T cells in GC and adjacent normal tissues. Then, flow cytometry was used to verify the data after collecting the peripheral blood, GC and adjacent normal tissues from 150 GC patients. Lastly, quantitative RT-PCR was performed to detect the expression of CD155, CD113, CD112 and TIGIT in six human GC cell lines and 631 GC patients in KM Plotter Database to conduct prognostic analysis. As results, we found that TIGIT and PD-1 were upregulated in GC tissues with high CD8 + T cells infiltration, while correlation analysis indicated they were in high-positive correlation. In addition, the flow cytometry analysis further showed that the high-expression of TIGIT in tumor microenvironment of GC could suppress the function of infiltrative CD8 + T cells, which leads to the escape of GC cells from immune killing. Furthermore, CD155 and CD112 were found abnormally upregulated in GC tissues and cell lines and the high expression of CD155, CD112 and TIGIT demonstrated poor prognosis results. In conclusion, these results provided potential therapeutic targets and prognostic biomarkers for treatment of GC in clinic. [ABSTRACT FROM AUTHOR]