Adenocarcinoma Of Stomach Research Articles

Functional activity of the monocyte immune link in gastric adenocarcinoma

Stomach cancer is in the top ten in terms of prevalence and ranks 4th in terms of causes of death worldwide. The most common and most aggressive variant of gastric cancer is adenocarcinoma. The monocytic link of immunity provides the main line of the body's fight against malignant cells, while in patients with adenocarcinoma it is insufficiently studied. The purpose of the study was to evaluate the functional activity of monocytes in patients with gastric adenocarcinoma at different stages of the disease.Individuals (n = 164) were examined, among whom 85 were diagnosed with stage I-IV stomach adenocarcinoma. The study also involved 79 apparently healthy donors. The functional activity and oxygen-dependent phagocytosis of monocytes were assessed by the chemiluminescent method. Luminol was used as a chemiluminescence inducer. The respiratory burst was activated with opsonized zymosan.In patients with stomach adenocarcinoma, at rest (spontaneous chemiluminescence), an increase in the time the curve reached the maximum intensity of chemiluminescence (Tmax = 7957 s), the area under the chemiluminescence curve (Squr = 0.2 x 106), the activation index (1.89 c. u.) and a decrease in the maximum value of chemiluminescence intensity (Imax = 424 c. u.) relative to the control group (Tmax = 5533 s, Squr = 0.011 x 106, activation index = 0.88 c. u., Imax = 424 c. u., p < 0.05) were seen. When chemiluminescence is induced in patients with stomach adenocarcinoma, a statistically significant predominance of Squr is fixed (0.46 x 106, in the control group Squr = 0.031 x 106). Also, in the group of patients with stomach adenocarcinoma, monocytic phagocytosis was reduced by more than 2 times (29% vs 84% in the control group, p < 0.05). When analyzing the studied parameters, depending on the stage of the disease, it was found that the violation of the chemiluminescent reaction in patients with stomach adenocarcinoma is fixed already at an early stage. At the same time, in patients with stage IV stomach adenocarcinoma, the indicators of spontaneous and induced chemiluminescence are more than 2 times different from those in the control group and patients at stage I of the disease. The identified features indicate a decrease in the effectiveness of immune reactions of the monocytic link in stomach adenocarcinoma already in the early stages of the disease and can be used to detect early signs of immune disorders and optimize therapeutic approaches in this disease.

Bidirectional Mediation Effects between Intratumoral Microbiome and Host DNA Methylation Changes Contribute to Stomach Adenocarcinoma.

The induction of aberrant DNA methylation is the major pathway by which Helicobacter pylori infection induces stomach adenocarcinoma (STAD). The involvement of the non-H. pylori gastric microbiota in this mechanism remains to be examined. RNA sequencing data, clinical information, and DNA methylation data were obtained from The Cancer Genome Atlas (TCGA) STAD project. The Kraken 2 pipeline was employed to explore the microbiome profiles. The microbiome was associated with occurrence, distal metastasis, and prognosis, and differential methylation changes related to distal metastasis and prognosis were analyzed. Bi-directional mediation effects of the intratumoral microbiome and host DNA methylation changes on the metastasis and prognosis of STAD were identified by mediation analysis. The expression of the ZNF215 gene was verified by real-time quantitative PCR (RT-qPCR). A cell counting kit 8 (CCK8) cell proliferation experiment and a cell clone formation experiment were used to evaluate the proliferation and invasion abilities of gastric cells. Our analysis revealed that H. pylori and other cancer-related microorganisms were related to the occurrence, progression, or prognosis of STAD. The related methylated genes were particularly enriched in related cancer pathways. Kytococcus sedentarius and Actinomyces oris, which interacted strongly with methylation changes in immune genes, were associated with prognosis. Cell experiments verified that Staphylococcus saccharolyticus could promote the proliferation and cloning of gastric cells by regulating the gene expression level of the ZNF215 gene. Our study suggested that the bi-directional mediation effect between intratumoral microorganisms and host epigenetics was key to the distal metastasis of cancer cells and survival deterioration in the tumor microenvironment of stomach tissues of patients with STAD. IMPORTANCE The burgeoning field of oncobiome research declared that members of the intratumoral microbiome besides Helicobacter pylori existed in tumor tissues and participated in the occurrence and development of gastric cancer, and the methylation of host DNA may be a potential target of microbes and their metabolites. Current research focuses mostly on species composition, but the functional genes of the members of the microbiota are also key to their interaction with the host. Therefore, we focused on characterizing the species composition and functional gene composition of microbes in gastric cancer, and we suggest that microbes may further participate in the occurrence and development of cancer by influencing abnormal epigenetic changes in the host. Some key bioinformatics analysis results were verified by in vitro experiments. Thus, we consider that the tumor microbiota-host epigenetic axis of gastric cancer microorganisms and the host explains the mechanism of the microbiota participating in cancer occurrence and development, and we make some verifiable experimental predictions.

A ferroptosis-related gene in Helicobacter pylori infection, SOCS1, serves as a potential prognostic biomarker and corresponds with tumor immune infiltration in stomach adenocarcinoma: In silico approach.

Helicobacter pylori (H. pylori) is a major risk factor for the stomach adenocarcinoma (STAD). This study aimed to investigate the potential role of a H. pylori infection-related gene, SOCS1, in STAD. Online available databases were analyzed to determine the expression, correlations with clinicopathologic parameters, patients' survival, and immunological characteristics of SOCS1 in TCGA-STAD or GEO datasets. Univariate and multivariate Cox regression analyses were used to determine independent risk factors, which were further integrated to establish a nomogram. A comparison of drug sensitivity was conducted for the chemotherapy responses between individuals with low- and high-SOCS1. Prediction of tumor response to checkpoint inhibitors was based on the tumor immunodeficiency and exclusion (TIDE) score. SOCS1 expression was significantly increased in both H. pylori-infected and STAD patients. Higher SOCS1 expression indicated an undesirable prognosis in STAD patients. SOCS1 upregulation was related to enhanced immune cell infiltrations and the upregulation of immune checkpoints in STAD patients. N stage, age and SOCS1 were identified as independent risk factors for higher mortality of STAD patients and confirmed using the nomogram. Drug sensitivity analyses demonstrated that high expression of SOCS1 in STAD patients could improve the sensitivity to chemotherapy. TIDE score showed that STAD patients with high SOCS1 expression would have superior response to immunotherapy. SOCS1 may act as a potential biomarker for uncovering the underlying mechanisms of gastric cancer. Increasing the activity of immunotherapy through ferroptosis-immunomodulation may be a viable strategy in STAD therapy.

P-367 The frequency and pattern of metachronous recurrence after endoscopic submucosal dissection for dysplasias and adenocarcinoma of stomach

P-367 The frequency and pattern of metachronous recurrence after endoscopic submucosal dissection for dysplasias and adenocarcinoma of stomach

Sex- and co-mutation-dependent prognosis of patients with SMARCA4-mutated malignancies.

e21031 Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A and STK11 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.3%) had a mut SMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%) and STK11 (12.8%) mutations. Male patients had substantially worse OS than female patients both among the entire cohort (HR = 1.76, [95% CI .94-3.30]) with a median OS of 3.0 versus 43.3 months ( P < .001), and among NSCLC cohort (HR = 9.72, [95% CI 2.19-43.19]) with a median OS of 2.75 months versus un-estimable ( P = .02). Among the entire cohort, mutp53 versus wtp53 (HR = 2.16, [95% CI 1.06-4.41]) and mutSTJ11 versus wtSTK11 (HR = 3.09, [95% CI 1.10-8.68]) were associated with worse OS. Among NSCLC cohort, mutp53 versus wtp53 (HR = .20, [.03-1.31]) and mutKRAS versus wtKRAS (HR = .13, [.01-1.03]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 4.38, [1.13-16.9]) and mutSTK11 versus wtSTK11 (HR = 18.1, [95% CI 1.30-251]) were associated with worse OS. Conclusions: Male patients had substantially worse prognosis than female patients, while MutTP53, mutKRAS, mutCDKN2A and mutSTK11 were differentially associated with prognosis among the entire cohort and among NSCLC cohort. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.

Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .

Enhanced descriptive captioning model for histopathological patches

AbstractThe interpretation of medical images into a natural language is a developing field of artificial intelligence (AI) called image captioning. This field integrates two branches of artificial intelligence which are computer vision and natural language processing. This is a challenging topic that goes beyond object recognition, segmentation, and classification since it demands an understanding of the relationships between various components in an image and how these objects function as visual representations. The content-based image retrieval (CBIR) uses an image captioning model to generate captions for the user query image. The common architecture of medical image captioning systems consists mainly of an image feature extractor subsystem followed by a caption generation lingual subsystem. We aim in this paper to build an optimized model for histopathological captions of stomach adenocarcinoma endoscopic biopsy specimens. For the image feature extraction subsystem, we did two evaluations; first, we tested 5 different vision models (VGG, ResNet, PVT, SWIN-Large, and ConvNEXT-Large) using (LSTM, RNN, and bidirectional-RNN) and then compare the vision models with (LSTM-without augmentation, LSTM-with augmentation and BioLinkBERT-Large as an embedding layer-with augmentation) to find the accurate one. Second, we tested 3 different concatenations of pairs of vision models (SWIN-Large, PVT_v2_b5, and ConvNEXT-Large) to get among them the most expressive extracted feature vector of the image. For the caption generation lingual subsystem, we tested a pre-trained language embedding model which is BioLinkBERT-Large compared to LSTM in both evaluations, to select from them the most accurate model. Our experiments showed that building a captioning system that uses a concatenation of the two models ConvNEXT-Large and PVT_v2_b5 as an image feature extractor, combined with the BioLinkBERT-Large language embedding model produces the best results among the other combinations.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

Efficacy of Neoadjuvant Chemotherapy on Locally Advanced Gastric Adenocarcinoma in Terms of Downstaging and Resectability in a Tertiary Cancer Hospital

Background: Neoadjuvant chemotherapy (NACT) in carcinoma stomach was introduced in an effort to eliminate micro-metastasis and to improve resectablity before surgery which improves R0 resection rates. The aim of the current study was to evaluate the effect of neoadjuvant chemotherapy on downstaging and resectability rate in locally advanced gastric cancer. Material & Methods: This was a single-center quasi-experimental study conducted in the Department of Surgical Oncology in collaboration with the Departments of Medical Oncology, Radiation oncology, and Pathology at the National Institute of Cancer Research and hospital, Dhaka, which is a tertiary care cancer hospital in Bangladesh, between January 2021 and June 2022.Patients with locally advanced adenocarcinoma stomach staged by contrast-enhanced computed tomography (CECT) were randomly included in this study by purposive sampling. Patients in Group I underwent upfront surgery Patients in Group II were started on neoadjuvant chemotherapy, either XELOX or FLOT regimen. Surgery was done following the response assessment CECT. We assessed R0 resection rate, age, sex, comorbidities, tumour size, TNM stage and complications were compared between the two groups. Response to NACT was assessed in Group II. Results: The mean age of patients in groups 1 & 2 was 56 ± 11.06 and 55.70 ± 10.46 years of age respectively (p > 0.05). Majority of the respondents (55/74) were male and 19 patients (26%) were female. Male to female ratio was (24/37 &31/37) in group 1 and (31/37 & 6/37) groups respectively (p > 0.05). Out of 37 patients who received NACT, in 9 patients (24.32%) complete response was noted. Partial response was found in 20 cases (54.05%), p-value (<.0001) while a stable disease was reported in three (8.1%) cases. 5 patients (13.51%) had progressive disease. In the upfront surgery group, R0 resection was feasible in 16 (43.2%) cases, and in the NACT plus surgery group, R0 resection was done in 29 (78.4%) cases. In group 1, R1 resection was done in considerable numbers (19/37) compared to group 2 (5/37), P=0.001. Three patients (8.1%) in group 2 and one (2.7) in group 1 had irresectable lesions. Conclusion: In this study it can be concluded that neoadjuvant chemotherapy could downstage tumour and increase tumor resectability rate in patients with locally-advanced gastric adenocarcinoma. However, further studies are necessary to confirm the effect of this modality on patients’ overall survival. We await survival analysis to further validate the role of NACT.

Inflammatory Ratios as Survival Prognostic Factors in Resectable Gastric Adenocarcinoma.

The purpose of the study was to assess the relationship between inflammatory biomarkers (NLR-neutrophil-to-lymphocyte ratio, PLR-platelet-to-lymphocyte ratio, LMR-lymphocyte-to-monocyte ratio, SII-systemic immune-inflammation index) and overall survival in gastric cancer patients. Over a six-year period (2016-2021), we conducted a longitudinal retrospective cohort research on 549 patients with resectable stomach adenocarcinoma. The overall survival was determined using the univariate and multivariate COX proportional hazards models. The age of the cohort varied between 30 and 89 years old, with an average age of 64.85 ± 10.51 years. Four hundred seventy-six patients (86.7%) had R0 resection margins. Eighty-nine (16.21%) subjects received neoadjuvant chemotherapy. Two hundred sixty-two (47.72%) patients died during the follow-up period. The median survival time in the cohort was 390 days. A significantly lower (p = 0.029-Logrank test) median survival was observed for R1 resections (355 days) in comparison with R0 resections (395 days). Significant differences in survival were observed regarding tumor differentiation, tumoral (T), and node (N) stage. No differences in survival were observed between the low or high value of inflammatory biomarkers (dichotomized by median value in the sample). In the COX univariate and multivariate regression models, elevated NLR proved an independent prognostic factor for lower overall survival [HR = 1.068, (95% CI 1.011-1.12)]. In this study, the other inflammatory ratios (PLR, LMR, and SII) did not prove as prognostic factors for gastric adenocarcinoma. In resectable gastric adenocarcinoma, elevated NLR before surgery was associated with lower overall survival. PLR, LMR, and SII had no prognostic value for the patient's survival.

Long Noncoding RNA ACTA2-AS1 Inhibits Cell Growth and Facilitates Apoptosis in Gastric Cancer by Binding with miR-6720-5p to Regulate ESRRB.

Gastric cancer (GC) is a common malignant tumor, posing a great threat to human's health and life. Previous studies have suggested aberrant expression of long non-coding RNAs (lncRNAs) in GC. This study elucidated the effects of lncRNA ACTA2-AS1 on the biological characteristics of GC. Gene expression in stomach adenocarcinoma (STAD) samples compared with normal tissues and the correlation between gene expression and prognosis of STAD patients were analyzed using bioinformatic tools. Gene expression at protein and mRNA levels in GC and normal cells was tested by western blotting and RT-qPCR. The subcellular localization of ACTA2-AS1 in AGS and HGC27 cells was identified by nuclear-cytoplasmic fractionation and FISH assay. EdU, CCK-8, flow cytometry analysis, TUNEL staining assays were conducted to evaluate the role of ACTA2-AS1 and ESRRB on GC cellular behaviors. The binding relationship among ACTA2-AS1, miR-6720-5p and ESRRB was verified by RNA pulldown, luciferase reporter assay and RIP assay. LncRNA ACTA2-AS1 was underexpressed in GC tissues and cell lines. ACTA2-AS1 elevation suppressed GC cell proliferation and induced apoptosis. Mechanistically, ACTA2-AS1 directly bound to miR-6720-5p and subsequently promoted the expression of target gene ESRRB in GC cells. Furthermore, ESRRB knockdown reversed the influence of ACTA2-AS1 overexpression on GC proliferation and apoptosis. ACTA2-AS1 plays an antioncogenic role in GC via binding with miR-6720-5p to regulate ESRRB expression.

Development of a novel copper metabolism-related risk model to predict prognosis and tumor microenvironment of patients with stomach adenocarcinoma.

Background: Stomach adenocarcinoma (STAD) is the fourth highest cause of cancer mortality worldwide. Alterations in copper metabolism are closely linked to cancer genesis and progression. We aim to identify the prognostic value of copper metabolism-related genes (CMRGs) in STAD and the characteristic of the tumor immune microenvironment (TIME) of the CMRG risk model. Methods: CMRGs were investigated in the STAD cohort from The Cancer Genome Atlas (TCGA) database. Then, the hub CMRGs were screened out with LASSO Cox regression, followed by the establishment of a risk model and validated by GSE84437 from the Expression Omnibus (GEO) database. The hub CMRGs were then utilized to create a nomogram. TMB (tumor mutation burden) and immune cell infiltration were investigated. To validate CMRGs in immunotherapy response prediction, immunophenoscore (IPS) and IMvigor210 cohort were employed. Finally, data from single-cell RNA sequencing (scRNA-seq) was utilized to depict the properties of the hub CMRGs. Results: There were 75 differentially expressed CMRGs identified, 6 of which were linked with OS. 5 hub CMRGs were selected by LASSO regression, followed by construction of the CMRG risk model. High-risk patients had a shorter life expectancy than those low-risk. The risk score independently predicted STAD survival through univariate and multivariate Cox regression analyses, with ROC calculation generating the highest results. This risk model was linked to immunocyte infiltration and showed a good prediction performance for STAD patients' survival. Furthermore, the high-risk group had lower TMB and somatic mutation counters and higher TIDE scores, but the low-risk group had greater IPS-PD-1 and IPS-CTLA4 immunotherapy prediction, indicating a higher immune checkpoint inhibitors (ICIs) response, which was corroborated by the IMvigor210 cohort. Furthermore, those with low and high risk showed differential susceptibility to anticancer drugs. Based on CMRGs, two subclusters were identified. Cluster 2 patients had superior clinical results. Finally, the copper metabolism-related TIME of STAD was concentrated in endothelium, fibroblasts, and macrophages. Conclusion: CMRG is a promising biomarker of prognosis for patients with STAD and can be used as a guide for immunotherapy.

The intratumor microbiome is associated with microsatellite instability.

Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among 451 CRC patients, our key finding was strong associations of multiple CRC-associated genera, including Dialister and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (hazard ratiomortality = 0.56, 95% confidence interval = 0.34 to 0.92, and hazard ratiomortality = 0.44, 95% confidence interval = 0.27 to 0.72), respectively, comparing higher relative to lower quantiles. Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.

Bioinformatics analyses suggest that mutations in COL12A1 and its miRNAs promote stomach adenocarcinoma via loss of COL12A1 suppression

Abstract Objectives Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. It is important to understand its molecular basis better and identify noninvasive biomarkers for targeted therapy. Usually, tumors contain driver genes or passenger genes, which can be regulated by microRNAs (miRNAs). However, the mechanism underlying the interaction between miRNA and their target genes in STAD has not been fully demonstrated. To date, no miRNA-targeted gene mutation sites that promote STAD progression have been reported, and there are no reports of the mutations within the 3′-UTR of COL12A1 that could contribute to STAD development. Methods Here, multiple genomic and transcriptomic profiles of STAD patients were downloaded from several reputable online databases and various analyses were conducted, including assessments of mutation rates, copy number variations (CNVs), single‐nucleotide polymorphisms (SNPs), RNA secondary structure, protein-protein interaction (PPI), pathway network, differentially expressed genes (DEGs), and patient survival rate. We aimed to evaluate impact of the SNPs on progression of stomach adenocarcinoma. Results We identified 22 critical DEGs involved in cell-cell and cell-matrix interaction. Seven of these key DEGs, including COL12A1, were associated with poorer overall survival. Interestingly, we found that COL12A1 was targeted by the miRNAs: hsa-miR-130b-5p (which carries the mutations rs1174814901 and rs761813865) and hsa-miR-18a-5p (which carries the mutation rs1198460870). These mutations lead to a change in the secondary structure of the miRNAs. And we also found that the miRNA target sites of COL12A1 were also mutated. These mutations at both miRNAs and COL12A1 likely attenuated their binding capability, leading to compensatory miRNA overexpression in the STAD patients. The miRNA overexpression was further found to be significantly associated with worse survival in STAD patients. Conclusions Our results suggest that mutations in Col12A1 and its miRNAs promote STAD via loss of COL12A1 suppression, providing new insight into the molecular mechanisms of STAD progression. This finding has significant implications for the development of novel noninvasive diagnostic, prognostic and therapeutic biomarkers.

The characteristics and clinical relevance of tumor fusion burden in non-EBV (+) gastric cancer with MSS

BackgroundNext-generation sequencing (NGS) is maturely applied for gene fusion detection. Although tumor fusion burden (TFB) has been identified as an immune marker for cancer, the relationship between these fusions and the immunogenicity and molecular characteristics of gastric cancer (GC) patients remains unclear. GCs have different clinical significance depending on their subtypes, and thus, this study aimed to investigate the characteristics and clinical relevance of TFB in non-Epstein–Barr-virus-positive (EBV+) GC with microsatellite stability (MSS).MethodsA total of 319 GC patients from The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD) and a cohort of 45-case from ENA (PRJEB25780) were included. The cohort characteristics and distribution of TFB among the patients were analyzed. Additionally, the correlations of TFB with mutation characteristics, pathway differences, relative abundance of immune cells, and prognosis were examined in the TCGA-STAD cohort of MSS and non-EBV (+) patients.ResultsWe observed that in the MSS and non-EBV (+) cohort, the TFB-low group exhibited significantly lower gene mutation frequency, gene copy number, loss of heterozygosity score, and tumor mutation burden than in the TFB-high group. Additionally, the TFB-low group exhibited a higher abundance of immune cells. Furthermore, the immune gene signatures were significantly upregulated in the TFB-low group, 2-year disease-specific survival was markedly increased in the TFB-low group compared with to the TFB-high group. The rates of TFB-low cases were significantly higher TFB-than high cases in durable clinical benefit (DCB) and response groups with pembrolizumab treatment. Low TFB may serve as a predictor of GC prognosis, and the TFB-low group exhibits higher immunogenicity.ConclusionIn conclusion, this study reveals that the TFB-based classification of GC patient may be instructive for individualized immunotherapy regimens.

Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies

Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A, STK11, and Keap1 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%), STK11 (mutSTK11, 12.8%), and Keap1 (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92–3.18]) with a median OS of 3.0 versus 43.3 months (p < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76–73.4]) with a median OS of 2.75 months versus un-estimable (p = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04–4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87–7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06–1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12–22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16–148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89–26.61}) were associated with worse OS. Conclusion: In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.

Identification of a novel de novo mutation of SETBP1 and new findings of SETBP1 in tumorgenesis

BackgroundIn the past decade, SETBP1 has attracted a lot of interest on that the same gene with different type or level (germline or somatic) of variants could provoke different pathologic consequences such as Schinzel-Giedon syndrome, SETBP1 Haploinsufficiency Disorder (SETBP1-HD) and myeloid malignancies. Whole exome sequencing was conducted to detect the etiology of a pregnant woman with mental retardation. As a new oncogene and potential marker of myeloid malignancies, somatic SETBP1 variants in other cancers were rarely studied. We performed a pan-cancer analysis of SETBP1 gene in different cancers for the first time.ResultsA novel heterozygous mutation of the SETBP1 gene (c.1724_1727del, p.D575Vfs*4) was found in the patient and the fetus and the mutation was predicted to result in a truncated protein. Reduced SETBP1 expression was associated with SETBP1-HD. The pan-cancer analysis of SETBP1 showed that SETBP1 overexpression should be given special attention in Bladder Urothelial Carcinoma (BLCA) and Stomach adenocarcinoma (STAD).ConclusionsThe de novo SETBP1 mutation was the genetic cause of SETBP1-HD in the family. BLCA and STAD might be related to SETBP1 overexpression.

M6A reader YTHDF3 is associated with clinical prognosis, related RNA signatures and immunosuppression in gastric cancer

BackgroundYTHDF3 as a N6-methyladenosine (m6A) reader participates in the development and progression of multiple cancer types, however, the prognosis, molecular biology and immune infiltration of YTHDF3 in gastric cancer (GC) have not been investigated. MethodsThe YTHDF3 expression profile and clinicopathological parameters of stomach adenocarcinoma (STAD) were downloaded from TCGA. The online websites and databases such as GEPIA2, cBioPortal, UALCAN, ImmuCellAl, xCell, TISIDB, GSCA were utilized for analysis of the association of YTHDF3 with STAD, including clinical prognosis, WGCNA and LASSO Cox regression analysis. Further functional assays such as RT-qPCR, Western blot, immunohistochemistry (IHC), immunofluorescence (IF), CCK-8, colony formation, EdU and Transwell assays were performed to determine the role of YTHDF3 in GC. ResultsWe found that YTHDF3 was upregulated in STAD tissue samples ascribed to its copy number amplification and associated with poor prognosis in patients with STAD. GO and KEGG analyses showed that YTHDF3-related differential genes were predominantly enriched in the proliferation, metabolism and immune signaling pathways. Knockdown of YTHDF3 repressed the growth and invasion of GC cells by inhibition of PI3K/AKT signaling. We then identified YTHDF3-related lncRNAs, miRNAs and mRNAs, and constructed their prognostic signatures in patients with STAD. Moreover, YTHDF3 associated with tumor immune infiltration such as CD8+ T cells, macrophages, Tregs, MHC molecules and chemokines, upregulated PD-L1 and CXCL1 and exerted a response to the immunotherapy in GC. ConclusionsYTHDF3 upregulation indicates poor prognosis and promotes GC cell growth and invasion by activating PI3K/AKT pathway and regulating immune microenvironment. The established YTHDF3-related signatures highlight the association of YTHDF3 with the clinical prognosis and immune cell infiltration in GC.

Depression-related RGS2 Gene Serves as a Novel Molecular Biomarker of Stomach Adenocarcinoma Prognosis and Immune Infiltration

Depression-related RGS2 Gene Serves as a Novel Molecular Biomarker of Stomach Adenocarcinoma Prognosis and Immune Infiltration

MAGED4B is a Poor Prognostic Marker of Stomach Adenocarcinoma and a Potential Therapeutic Target for Stomach Adenocarcinoma Tumorigenesis.

Gastric cancer is the second most common cause of cancer death worldwide with poor overall prognosis. It is important to study the molecular mechanism of stomach adenocarcinoma (STAD). MAGED4B, a member of the melanoma antigen gene (MAGE) family, is highly expressed in many tumor cells and is associated with tumor progression. Its prognostic value in and the function of the encoded protein are still unclear. The data of 415 STAD tissues was retrieved from TCGA database, and the expression level of MAGED4B mRNA was evaluated. The correlation between the expression of MAGED4B mRNA and the progression free survival (PFS) time of STAD patients was evaluated by Kaplan Meier analysis. The STAD cell lines with overexpressed and silent MAGED4B were constructed, and the effects of MAGED4B on the viability, migration and proliferation were evaluated by the CCK-8, scratch test and EDU test. The flow cytometry was used to detect apoptosis with overexpressed and silent MAGED4B under the cisplatin treatment, and WB was used to detect the expressions of related proteins, such as TNF-α. The expression level of MAGED4B mRNA in the STAD tissues was higher than that in the normal tissues, and its high expression was related to poor PFS. The overexpression of MAGED4B in the STAD cell lines can promote the vitality, motility and proliferation of the STAD cells, while the silencing of MAGED4B can inhibit the above three cell functions of the STAD cells. The overexpression of MAGED4B can reduce the cisplatin induced apoptosis and increase the cisplatin IC50; the silencing of MAGED4B can promote the cisplatin induced apoptosis and reduce the cisplatin IC50. The overexpression of MAGED4B reduced the protein levels of TRIM27 and TNF- α. MAGED4B could be a valuable prognostic biomarker and a therapeutic target for gastric adenocarcinoma of great interest.