• Humans
• Machine Learning
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Transcription Factor AP-1/metabolism
• Transcription Factor AP-1/genetics
• Cell Line, Tumor
• Fibrosis/genetics
• Core Binding Factor Alpha 1 Subunit/genetics
• Core Binding Factor Alpha 1 Subunit/metabolism
• DNA Copy Number Variations
• Core Binding Factor Alpha 2 Subunit

• R01 HG012367 NHGRI NIH HHS
• MOH-000967-00 Medical Research Council
• MOH-OFLCG18MAY-0003 Medical Research Council
• National Institutes of Health–National Human Genome Research Institute
• National Medical Research Council
• National Research Foundation, Singapore, and Singapore Ministry of Health's National Medical Research Council

• Berberis vulgaris
• apoptosis
• cell cycle
• drug interactions
• gastric cancer
• magnoflorine
• proliferation
• zebrafish

• Animals
• Humans
• Docetaxel/pharmacology
• Docetaxel/therapeutic use
• Stomach Neoplasms/pathology
• Zebrafish
• Cell Proliferation
• Cell Line, Tumor
• Apoptosis
• Adenocarcinoma/drug therapy

• DS 440, DS 24, DS 448, DS 715 Medical Univeristy of Lublin, Poland

• gastric cancer
• gene expression
• prognosis
• risk classification
• score

• NETs-related signature
• NETs-related signature predicts the prognosis
• gastric cancer
• immune therapy
• neutrophil extracellular traps

• National Natural Science Foundation of China

• SLITRK5
• epilepsy
• neurite outgrowth
• synaptogenesis
• temporal lobe epilepsy

• Animals
• Rats
• Disease Models, Animal
• Epilepsy/chemically induced
• Epilepsy/metabolism
• Epilepsy, Temporal Lobe/chemically induced
• Hippocampus/metabolism
• Neocortex/metabolism
• Pilocarpine/toxicity
• Pilocarpine/metabolism
• Rats, Sprague-Dawley
• Seizures/metabolism
• Up-Regulation

• Cancer biomarkers
• Colorectal cancer
• Computational oncology
• Molecular signature
• Multi-omics

• Molor-dabos-4
• Mongolian medicine
• gastric ulcer
• mechanism of action
• transcriptomic analysis

• Rats
• Animals
• Stomach Ulcer/chemically induced
• Stomach Ulcer/drug therapy
• Stomach Ulcer/genetics
• Indomethacin/adverse effects
• Antioxidants/pharmacology
• Tumor Necrosis Factor-alpha/genetics
• Medicine, Mongolian Traditional
• RNA-Seq
• Pepsin A/adverse effects
• Oxytocin/genetics
• Interleukin-6/genetics
• Superoxide Dismutase
• Cytokines/genetics
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Arginine
• Proline

• CAFS-score
• CAFs gene
• Gastric cancer
• immune microenvironment infiltration
• immune therapy

• Cancer-Associated Fibroblasts/metabolism
• Humans
• Monocytes/metabolism
• Prognosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/therapy
• Tumor Microenvironment/genetics

• Humans
• Attention Deficit Disorder with Hyperactivity/metabolism
• Central Nervous System/metabolism
• Membrane Proteins/metabolism
• Nerve Tissue Proteins/metabolism
• Neurons/metabolism
• Obsessive-Compulsive Disorder/metabolism

• GEO
• TCGA
• hub genes
• identification
• stomach adenocarcinoma

Two datasets were used as training and validation cohorts to establish the predictive model. We used three types of screening criteria: background analysis, pathway analysis, and functional analysis provided by the cBioportal website. Fisher's exact test and multivariable logistic regression were performed to screen out related genes. Furthermore, we performed receiver operating characteristic (ROC) and Kaplan–Meier curve analyses to evaluate the correlation between the selected genes and overall survival.

We screened five genes (KNL1, NRXN1, C6, CCDC169-SOHLH2, and TTN) that were highly related to recurrence of GC. The area under the receiver operating characteristic (ROC) curve was 0.813, which was much higher than that of the baseline model (AUC = 0.699). This result suggested that the mutation of five selected genes had a significant effect on the prediction of recurrence compared with other factors (age, stages, history, etc.). Furthermore, the Kaplan-Meier estimator also revealed that the mutation of five genes positively correlated with patient survival.

The patients who have mutations in these five genes may experience longer survival than those who do not have mutations. This five-gene panel will likely be a practical tool for prognostic evaluation and will provide another possible way for clinicians to determine therapy.

TP53 is the most frequently mutated gene in gastric cancer and it can be potentially used for gastric cancer diagnosis and screening. However, standardized clinical approaches that could accurately and cost-effectively detect TP53 mutations in gastric cancer are largely lagged behind.

We conducted next-generation sequencing (NGS) analysis of 425 cancer-related genes in 42 gastric cancer patients in our cohort. A 1313-patient cohort derived from the cBioPortal database was used for validation. We performed immunohistochemistry (IHC) staining with four commonly used p53 antibodies, and the NGS results were used as the gold standard to optimize the IHC threshold for each antibody.

By NGS analysis, we found that around 80% of gastric cancer patients in our cohort harbored TP53 alterations. Genetic alterations of BRCA1/2 or KMT2B were mostly exclusive with TP53 mutations, so were the MSI status or low grade of tumors. These results were further validated using the data from cBioPortal. We then used the NGS-derived TP53 status to optimize four commonly used IHC antibodies for detecting TP53 mutations. We showed that all antibodies could achieve more than 93% accuracy when proper IHC positivity thresholds were used, especially for the SP5 antibody that could reach 100% sensitivity and specificity with the 20% threshold.

Our results indicated that exclusivity between TP53 and BRCA mutations could be potentially used as a cost-effective way to predict BRCA status. Also, setting proper IHC thresholds for each specific antibody is critical to accurately detect TP53 mutations and facilitate disease diagnosis.

• TP53
• co-mutation
• gastric cancer
• immunohistochemistry threshold
• next-generation sequencing

• Ewing sarcoma
• Ewing sarcoma stem-like cells
• Neurexin-1
• Patient-derived cells

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Bone Neoplasms/genetics
• Bone Neoplasms/metabolism
• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/metabolism
• Cell Adhesion Molecules, Neuronal/genetics
• Cell Adhesion Molecules, Neuronal/metabolism
• Cell Line, Tumor
• Child
• Doxorubicin/pharmacology
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Neural Cell Adhesion Molecules/genetics
• Neural Cell Adhesion Molecules/metabolism
• Prognosis
• Sarcoma, Ewing/genetics
• Sarcoma, Ewing/metabolism
• Sequence Analysis, RNA/methods
• Transcriptome/genetics
• Tumor Cells, Cultured
• Vincristine/pharmacology

• 602856 FP7
• Bone Cancer Research Trust
• FP7
• Ewing Sarcoma Research Trust (GB)
• Faculty of Medicine and Health, University of Leeds

Background: Long non-coding RNAs are critical to hepatocellular carcinoma (HCC) developments. LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) is a new regulator in several tumors. However, the mechanism by which PITPNA-AS1 mediates the tumorigenesis of HCC remains unclear.

Methods: RT-qPCR was used to detect the level of PITPNA-AS1 in HCC specimens and cells. The biological functions of PITPNA-AS1 were explored by several functional experiments in vivo and in vitro. The binding relationship among PITPNA-AS1, miR-448 and ROCK1 were studied by Luciferase assay and pull-down assays.

Results: We found that PITPNA-AS1 expressions were distinctly upregulated in both HCC specimens and cell lines. High PITPNA-AS1 levels were an unfavorable biomarker for patients with HCC. Functionally, knockdown of PITPNA-AS1 suppressed the proliferation, migration and invasion of HCC cells. Mechanistically, PITPNA-AS1 functioned as competing endogenous RNA to increase ROCK1 expressions via sponging miR-448.

Conclusion: The newly identified PITPNA-AS/miR-448/ROCK1 axis promoted the oncogenicity of HCC cells. This novel axis is likely to be a promising HCC therapeutic aim.

• LncRNA PITPNA-AS1
• ROCK1
• biomarker
• hepatocellular carcinoma
• miR-448

Growing attention have been paid to the relationship between TP53 and tumor immunophenotype, but there are still lacking enough search on the field of gastric cancer (GC).

We identified differential expressed immune-related genes (DEIRGs) between the TP53-altered GC samples (n = 183) and without TP53-altered GC samples (n = 192) in The Cancer Genome Atlas and paired them. In the TCGA cohort (n = 350), a risk score was determined through univariate and multivariate cox regression and Lasso regression analysis. Patients were divided into two groups, high-risk and low-risk, based on the median risk score. Four independent cohorts (GSE84437,n = 431; GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 100) from the Gene Expression Omnibus (GEO) database were used to validate the reliability and universal applicability of the model.

The signature contained 11 gene pairs showed good performance in predicting progression-free survival (PFS), disease-free survival (DFS), disease special survival (DSS), and the overall survival (OS) for GC patients in the TCGA cohort. The subgroup analysis showed that the signature was suitable for GC patients with different characteristics. The signature could capable of distinguish GC patients with good prognosis and poor prognosis in all four independent external validation cohorts. The high- and low-risk groups differed significantly in the proportion of several immune cell infiltration, especially for the T cells memory resting, T cells memory activated and follicular helper, and Macrophage M0, which was also related to the prognosis of GC patients.

The present work proposed an innovative system for evaluating the prognosis of gastric cancer. Considering its stability and general applicability, which may become a widely used tool in clinical practice.

The online version contains supplementary material available at 10.1186/s12967-021-02846-x.

• Gastric cancer
• Gene pairs
• Immune
• Prognostic
• Signature

Esophageal cancer (EC) involves many genomic, epigenetic and transcriptomic disorders, which play key roles in the heterogeneous progression of cancer. However, the study of EC with multi-omics has not been conducted. This study identified a high consistency between DNA copy number variations and abnormal methylations in EC by analyzing genomics, epigenetics and transcriptomics data and investigating mutual correlations of DNA copy number variation, methylation and gene expressions, and stratified copy number variation genes (CNV-Gs) and methylation genes (MET-Gs). The methylation, CNVs and expression profiles of CNV-Gs and MET-Gs were analyzed by consistent clustering using iCluster integration, here, we determined three subtypes (iC1, iC2, iC3) with different molecular traits, prognostic characteristics and tumor immune microenvironment features. We also identified 4 prognostic genes (CLDN3, FAM221A, GDF15 and YBX2) differentially expressed in the three subtypes, and could therefore be used as representative biomarkers for the three subtypes of EC. In conclusion, by performing comprehensive analysis on genomic, epigenetic and transcriptomic regulations, the current study provided new insights into the multilayer molecular and pathological traits of EC, and contributed to the precision medication for EC patients.

• copy number variation
• esophageal cancer
• methylation
• multi-omics associated analysis
• prognostic markers

The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers.

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.

• biomarker
• cell death
• chemotherapy
• gastric cancer
• immunotherapy
• isoforms
• metastasis
• p53 family
• personalized therapy
• tumor ecosystem

Gastric cancer (GC) is a complex disease linked to a series of environmental factors and unhealthy lifestyle habits, and especially to genetic alterations. GC represents the second leading cause of cancer-related deaths worldwide. Its onset is subtle, and the majority of patients are diagnosed once the cancer is already advanced. In recent years, there have been innovations in the management of advanced GC including the introduction of new classifications based on its molecular characteristics. Thanks to new technologies such as next-generation sequencing and microarray, the Cancer Genome Atlas and Asian Cancer Research Group classifications have also paved the way for precision medicine in GC, making it possible to integrate diagnostic and therapeutic methods. Among the objectives of the subdivision of GC into subtypes is to select patients in whom molecular targeted drugs can achieve the best results; many lines of research have been initiated to this end. After phase III clinical trials, trastuzumab, anti-Erb-B2 receptor tyrosine kinase 2 (commonly known as ERBB2) and ramucirumab, anti-vascular endothelial growth factor receptor 2 (commonly known as VEGFR2) monoclonal antibodies, were approved and introduced into first- and second-line therapies for patients with advanced/metastatic GC. However, the heterogeneity of this neoplasia makes the practical application of such approaches difficult. Unfortunately, scientific progress has not been matched by progress in clinical practice in terms of significant improvements in prognosis. Survival continues to be low in contrast to the reduction in deaths from many common cancers such as colorectal, lung, breast, and prostate cancers. Although several target molecules have been identified on which targeted drugs can act and novel products have been introduced into experimental therapeutic protocols, the overall approach to treating advanced stage GC has not substantially changed. Currently, surgical resection with adjuvant or neoadjuvant radiotherapy and chemotherapy are the most effective treatments for this disease. Future research should not underestimate the heterogeneity of GC when developing diagnostic and therapeutic strategies aimed toward improving patient survival.

• Gastric cancer
• Molecular characterization
• Biomarkers
• Precision medicine
• Targeted therapy

• Computational Biology
• Databases, Genetic
• Humans
• Kaplan-Meier Estimate
• Mutation, Missense/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Tumor Suppressor Protein p53/genetics

In this study, we found that RAB39A, a member of the RAS oncogene family, was selectively expressed in cancer cells of different histotypes, by analyzing gene expression in human osteosarcoma cells and the cancer stem cells (CSCs) and by comparing them with normal cells through global transcriptomics and principal component analyses. We further validated RAB39A as a therapeutic target, by silencing its expression. The silencing impaired cancer stemness and spherogenic ability in vitro, as well as tumorigenesis in vivo. RNA-seq analyses in the silenced spheres suggested that RAB39A is associated downstream with RXRB and KLF4. Notably, RXRB expression was inhibited in RAB39A-silenced CSCs. Induced overexpression of RXRB in RAB39A-silenced cells restored spherogenic ability and tumorigenesis, confirming RXRB as a major effector of RAB39A. Quantitative RT-PCR analysis of ∼400 human cancer tissues showed that RAB39A was highly expressed in sarcomas and in malignancies of lymphoid, adrenal and testicular tissues. Our data provide the rationale for targeting of the RAB39A-RXRB axis as a therapy for aggressive cancers.

• RAB39A
• RXRB
• cancer stem cell
• spherogenicity
• tumorigenesis