Survival Outcomes In Gastric Cancer Research Articles

Identification of a novel prognostic model for gastric cancer utilizing glutamine-related genes

BackgroundGlutamine metabolism presents a promising avenue for cancer prevention and treatment, but the underlying mechanisms in gastric cancer (GC) progression remain elusive. MethodsThe TCGA-STAD and GEO GSE62254 datasets, containing gene expression, clinical information, and survival outcomes of GC, were meticulously examined. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to excavate a key module (MEturquoise), which was used to intersect with glutamine metabolism-related genes (GMRGs) and differentially expressed genes (DEGs) to identify differentially expressed GMRGs (DE-GMRGs). LASSO and Cox Univariate analyses were implemented to determine risk model genes. Correlation of the risk model with clinical parameters, pathways, and tumor immune microenvironments, was analyzed, and its prognostic independence was validated by Cox analyses. Finally, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to validate the expression levels of MYB, LRFN4, LMNB2, and SLC1A5 in GC and para-carcinoma tissue. ResultsThe excavation of 4521 DEGs led to the discovery of the key MEturquoise module, which exhibited robust correlations with GC traits. The intersection analysis identified 42 DE-GMRGs, among which six genes showed consistency. Further LASSO analysis established MYB, LRFN4, LMNB2, and SLC1A5 as pivotal risk model genes. The risk model demonstrated associations with oncogenic and metabolism-related pathways, inversely correlating with responses to immune checkpoint blockade therapies. This risk model, together with “age”, was validated to be an independent prognostic factor for GC. RT-qPCR result indicated that MYB, LRFN4, LMNB2, and SLC1A5 expressions were remarkably up-regulated in GC tissues comparison with para-carcinoma tissue. ConclusionThe present study has generated a novel risk module containing four DE-GMRGs for predicting the prognosis and the response to immune checkpoint blockade treatments for GC. This risk model provides new insights into the involvement of glutamine metabolism in GC, warranting further investigation.

Abstract 5583: Helicobacter pylori induces the wee1, promoting immune suppressive in human gastric adenocarcinoma

Abstract Background: Gastric cancer (GC) is the fourth most common cause of cancer-related death worldwide. GC has a dismal 5-year survival rate of about 32%. Helicobacter pylori (H. pylori) infection is the strongest risk factor for gastric carcinogenesis. 75-90% of gastric cancer patients exhibit positive H. pylori serology. WEE1 is a nuclear kinase that regulates cell cycle progression by inhibiting cyclin-dependent kinases. Methods & Results: Analysis of non-cancer normal stomach tissue (n=360) and human GC samples (n=1221) identified that WEE1 mRNA was significantly overexpressed in GC. Using immunohistochemistry (IHC) staining in 41 normal and 44 GC human samples, the data indicated that WEE1 protein was significantly overexpressed in GC. Western blot and immunofluorescence (IF) staining confirmed that H. pylori infection induces WEE1 overexpression in GC cells with an unexpected cytosolic localization of WEE1 in GC cells. Tff1 knockout GC mouse model (Tff1-/-) was infected with mouse-adapted H. pylori strain PMSS1. Western blot and immunohistochemistry data demonstrated that H. pylori infection induced WEE1 expression in Tff1 -/- HGD/cancer mouse gastric tissues compared to control Tff1 -/- mouse stomach. To study how H. pylori infection induces WEE1 in GC, analysis from miRTAR, Target Scan, and miRDB demonstrated that WEE1 is predicted to be targeted by miR-497-5p. Using qRT-PCR analysis, we assessed 30 normal and 30 GC human tissue samples, revealing a pronounced downregulation of miR-497-5p in GC specimens. Western blot analysis confirmed that the restoration of miR-497-5p in GC cells markedly reduced WEE1 protein expression. Interestingly, H. pylori infection further decreased miR-497-5p levels in GC cells, upregulating WEE1 protein expression. Since the miR-497-5P host gene promoter region contains CpG islands, we confirmed that treatment with 5 Azacytidine (demethylating agent) or DNMT1 knockdown induced expression of miR-497-5p with decreased WEE1 level in GC cells. Furthermore, our preliminary results indicate that aberrant WEE1 overexpression in GC demonstrates a significant positive correlation with immune-suppression gene signatures, underscoring its predictive value for unfavorable patient survival outcomes in GC. Using the TFF1 knockout mouse GC model, we found that WEE1 inhibition notably decreases the number and activation of CD4+ and CD8+ T cells in neoplastic gastric tissues. These findings also indicate a crucial relationship between WEE1 and the immunosuppressive microenvironment in GC, establishing WEE1 as a promising therapeutic target to enhance therapeutic efficacy and overcome immunotherapy resistance in GC. Conclusions: Our findings demonstrated a novel mechanism in which H. pylori activates the WEE1 in GC, promoting an immune suppressive microenvironment. WEE1 inhibition with immunotherapy could be a promising therapeutic method for GC patients. Citation Format: Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Wael El-Rifai, Zheng Chen. Helicobacter pylori induces the wee1, promoting immune suppressive in human gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5583.

A Comparative Analysis of Laparoscopic Gastrectomy Versus Laparoscopic-Assisted Gastrectomy: The Overall and Disease-Free Survival.

Gastric cancer remains a significant global health challenge with varied survival rates, emphasizing the need for research into effective surgical treatments. In this retrospective study, we compared the 72-month overall and disease-free survival between laparoscopic gastrectomy (LG) and laparoscopic-assisted gastrectomy (AG) in a cohort of 139 patients treated for gastric cancer. The analysis revealed that patients undergoing LG exhibited a significantly higher overall survival rate at 72 months compared to those undergoing AG. Although disease-free survival rates were comparable between the two groups, LG showed a marginal advantage. Subgroup analyses based on the type of gastrectomy and anastomosis demonstrated varied survival probabilities, with laparoscopic-assisted partial gastrectomy yielding the most favorable outcomes. These results highlight the importance of the choice of surgical technique in influencing survival outcomes in gastric cancer.

BNIP3 and DAPK1 methylation in peripheral blood leucocytes are noninvasive biomarkers for gastric cancer

ObjectiveThe objective of this study is to comprehensively investigate the potential value of BNIP3 and DAPK1 methylation in peripheral blood leukocytes as a non-invasive biomarker for the detection of gastric cancer (GC), prediction of chemotherapy efficacy, and prognosis assessment. Patients and methodsInitially, multiple bioinformatic analyses were employed to explore the genetic landscape and biological effects of BNIP3 and DAPK1 in GC tissues. Subsequently, case-control and prospective follow-up studies were conducted to compare the differences in BNIP3 and DAPK1 methylation levels in peripheral blood leukocytes among GC patients and healthy controls, as well as between patients exhibiting sensitivity and resistance to platinum plus fluorouracil treatment, and between patients with varying survival outcomes of GC. Additionally, several predictive nomograms were constructed based on the identified CpG sites and relevant clinical parameters to forecast the occurrence of GC, chemotherapy efficacy, and prognosis. ResultsThe upregulation of BNIP3 and DAPK1 was found to be associated with the development and poorer survival outcomes of GC. Furthermore, the expression of BNIP3/DAPK1 exhibited an inverse relationship with their DNA methylation levels and demonstrated a positive correlation with immune cell infiltration, as well as the IC50 values of 5-Fluorouracil and Cisplatin in GC tissues. Increased infiltration of macrophages in the high-expression groups was observed to be linked to unfavorable GC survival. In the case-control and follow-up studies, lower methylation levels of BNIP3 and DAPK1 were identified in the peripheral leukocytes of GC patients compared to healthy controls. Hypomethylation was also associated with more aggressive subtypes, diminished chemotherapy efficacy, and poorer survival outcomes in GC. ConclusionThe DNA methylation of BNIP3 and DAPK1 in peripheral blood leukocytes holds promise as a novel non-invasive biomarker for predicting the occurrence of GC, chemotherapy efficacy, and prognosis assessment.

FJX1 overexpression is associated with poor prognosis and promotes gastric cancer proliferation via the PI3K/AKT signaling pathway

To investigate the expression of four-jointed box kinase 1 (FJX1) in gastric cancer (GC), its correlation with survival outcomes of the patients, and its role in GC progression. The expression level of FJX1 in GC tissues and normal gastric mucosal tissues and its correlation with the survival outcomes of GC patients were analyzed using TCGA and GEO database GC cohort. Immunohistochemistry was used to detect FJX1 expression level in clinical specimens of GC tissue, and its correlations with the patients' clinicopathological parameters and prognosis were analyzed. Bioinformatic analysis was performed to identify the potential pathways of FJX1 in GC. The effects of FJX1 overexpression or FJX1 silencing on GC cell proliferation and expressions of proliferation-related proteins, PI3K, AKT, p-PI3K, and p-AKT were evaluated using CCK-8 assay and Western blotting. The effect of FJX1 overexpression on GC cell tumorigenicity was evaluated in nude mice. GC tissues showed significantly higher expressions of FJX1 mRNA and protein compared with normal gastric mucosa tissues (P < 0.05). The high expression of FJX1 was associated with poor prognosis of GC patients (P < 0.05) and served as an independent risk factor for poor survival outcomes in GC (P < 0.05). FJX1 was expressed mainly in the cytoplasm of GC cells in positive correlation with Ki67 expression (R=0.34, P < 0.05), and was correlated with CA199 levels, depth of tumor infiltration and lymph node metastasis of GC (P < 0.05). In the cell experiment, FJX1 level was shown to regulate the expressions of Ki67 and PCNA and GC cell proliferation (P < 0.05). Gene set enrichment analysis indicated that the PI3K/AKT pathway potentially mediated the effect of FJX1, which regulated the expressions of PI3K and AKT and their phosphorylated proteins. In nude mice, FJX1 overexpression in GC cells significantly promoted the growth of the transplanted tumors (P < 0.05). FJX1 is highly expressed in GC tissues and is correlated with poor prognosis of GC patients. FJX1 overexpression promotes GC cell proliferation through the PI3K/AKT signaling pathway, and may serve as a potential prognostic biomarker and therapeutic target for GC.

Construction and validation of a prognosis signature based on the immune microenvironment in gastric cancer.

Gastric cancer (GC) is an aggressive malignant tumor with a high degree of heterogeneity, and its immune microenvironment is closely associated with tumor growth, development and drug resistance. Therefore, a classification system of gastric cancer based explicitly on the immune microenvironment context might enrich the strategy for gastric cancer prognosis and therapy. A total of 668 GC patients were collected from TCGA-STAD (n = 350), GSE15459 (n = 192), GSE57303 (n = 70) and GSE34942 (n = 56) datasets. Three immune-related subtypes (immunity-H, -M, and -L) were identified by hierarchical cluster analysis based on the ssGSEA score of 29 immune microenvironment-related gene sets. The immune microenvironment-related prognosis signature (IMPS) was constructed via univariate Cox regression, Lasso-Cox regression and multivariate Cox regression, and nomogram model combining IMPS and clinical variables was further constructed by the "rms" package. RT-PCR was applied to validate the expression of 7 IMPS genes between two human GC cell lines (AGS and MKN45) and one normal gastric epithelial cell line (GES-1). The patients classified as immunity-H subtype exhibited highly expressed immune checkpoint and HLA-related genes, with enriched naïve B cells, M1 macrophages and CD8 T cells. We further constructed and validated a 7-gene (CTLA4, CLDN6, EMB, GPR15, ENTPD2, VWF and AKR1B1) prognosis signature, termed as IMPS. The patients with higher IMPS expression were more likely to be associated with higher pathology grade, more advanced TNM stages, higher T and N stage, and higher ratio of death. In addition, the prediction values of the combined nomogram in predicting 1-year (AUC = 0.750), 3-year (AUC = 0.764) and 5-year (AUC = 0.802) OS was higher than IMPS and individual clinical characteristics. The IMPS is a novel prognosis signature associated with the immune microenvironment and clinical characteristics. The IMPS and the combined nomogram model provide a relatively reliable predictive index for predicting the survival outcomes of gastric cancer.

Sex Disparity in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis aimed to ascertain whether sex-based differences influence clinicopathological characteristics and survival outcomes of gastric cancer patients. Gastric cancer in females has received less attention than in males. Clinicopathological features and survival outcomes of females with gastric cancer have been reported in several studies with controversial results. We systematically reviewed clinical studies from PubMed, Cochrane Library, Embase, and Web of Science published up to June 2022. The effect sizes of the included studies were estimated using odds ratios (ORs). Heterogeneity was investigated using the χ2 and I 2 tests, while sensitivity analyses were performed to identify the source of substantial heterogeneity. All data used in this study were obtained from previously published studies obviating the need for ethical approval and patient consent. Seventy-six studies with 775,003 gastric cancer patients were included in the meta-analysis. Gastric cancer patients were less likely to be females (P < 0.00001). Female patients were younger in age (P < 0.00001) and showed a higher percentage of distal (P < 0.00001), non-cardia (P < 0.00001), undifferentiated (P < 0.00001), diffuse (P < 0.00001), and signet-ring cell carcinoma (P < 0.00001). Female patients showed better prognosis in both 3-year (P = 0.0003) and 5-year overall survival (OS) (P < 0.00001), especially White patients. However, females were associated with lower 5-year OS relative to males in the younger patients (P = 0.0001). In conclusion, gender differences were observed in clinicopathological characteristics and survival outcomes of gastric cancer. Different management of therapy will become necessary for different genders.

Baseline QOL, QOL-relevant HLA-restricted HERV gene-derived peptides, and survival outcomes in gastric cancer

Baseline QOL, QOL-relevant HLA-restricted HERV gene-derived peptides, and survival outcomes in gastric cancer

Tumor Microenvironment Characterization for Assessment of Recurrence and Survival Outcome in Gastric Cancer to Predict Chemotherapy and Immunotherapy Response.

BackgroundThe tumor microenvironment (TME) is crucial for tumor recurrence, prognosis, and therapeutic responses. We comprehensively investigated the TME characterization associated with relapse and survival outcomes of gastric cancer (GC) to predict chemotherapy and immunotherapy response.MethodsA total of 2,456 GC patients with complete gene-expression data and clinical annotations from twelve cohorts were included. The TME characteristics were evaluated using three proposed computational algorithms. We then developed a TME-classifier, a TME-cluster, and a TME-based risk score for the assessment of tumor recurrence and prognosis in patients with GC to predict chemotherapy and immunotherapy response.ResultsPatients with tumor recurrence presented with inactive immunogenicity, namely, high infiltration of tumor-associated stromal cells, low infiltration of tumor-associated immunoactivated lymphocytes, high stromal score, and low immune score. The TME-classifier of 4 subtypes with distinct clinicopathology, genomic, and molecular characteristics was significantly associated with tumor recurrence (P = 0.002), disease-free survival (DFS, P <0.001), and overall survival (OS, P <0.001) adjusted by confounding variables in 1,193 stage I–III GC patients who underwent potential radical surgery. The TME cluster and TME-based risk score can also predict DFS (P <0.001) and OS (P <0.001). More importantly, we found that patients in the TMEclassifier-A, TMEclassifier-C, and TMEclassifier-D groups benefited from adjuvant chemotherapy, and patients in the TMEclassifier-B group without chemotherapy benefit responded best to pembrolizumab treatment (PD-1 inhibitor), followed by patients in the TMEclassifier-A, while patients in the C and D groups of the TMEclassifier responded poorly to immunotherapy.ConclusionWe determined that TME characterization is significantly associated with tumor recurrence and prognosis. The TME-classifier we proposed can guide individualized chemotherapy and immunotherapy decision-making.

Significance of Preoperative Prognostic Nutritional Index in the Perioperative Management of Gastric Cancer

BackgroundMalnutrition leads to accelerated tumor progression through the suppression of tumor immunity. The present study examined the significance of the preoperative prognostic nutritional index (PNI) for predicting postoperative survival outcomes in gastric cancer (GC). MethodsA total of 447 patients who underwent curative gastrectomy for GC were included in the present study. PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte counts (per mm3). The prognostic impact of preoperative PNI was examined using two multivariate analysis models. ResultsThe optimal cutoff value of preoperative PNI for predicting overall survival (OS) was 48 based on a receiver operating characteristic curve. The 5-year OS rate was 59.5% in the PNI<48 group and 91.3% in the PNI≥48 group (p<0.001). In the first multivariate survival analysis where all explanatory variables were composed of preoperative factors alone, a PNI<48 (hazard ratio [HR] 3.33; 95% confidence interval [CI] 2.01–5.56, p<0.001), upper-third GC and cT2–T4 were identified as independent indicators of a poor OS. In the second survival analysis where explanatory variables were composed of preoperative, intraoperative, and pathological factors, a PNI<48 (HR 2.80; 95% CI 1.65–4.78, p<0.001), hypertension, open gastrectomy, intraoperative blood loss≥100g, pT2–T4, and pN+ were independent prognostic factors. ConclusionPreoperative PNI may be a useful predictor of postoperative survival outcomes both before and immediately after surgery in GC. Appropriate perioperative interventions and the meticulous surveillance of GC relapse are necessary for patients with PNI<48.

Identification of a Gene Prognostic Model of Gastric Cancer Based on Analysis of Tumor Mutation Burden.

Introduction: Gastric cancer is one of the most common cancers. Although some progress has been made in the treatment of gastric cancer with the improvement of surgical methods and the application of immunotherapy, the prognosis of gastric cancer patients is still unsatisfactory. In recent years, there has been increasing evidence that tumor mutational load (TMB) is strongly associated with survival outcomes and response to immunotherapy. Given the variable response of patients to immunotherapy, it is important to investigate clinical significance of TMB and explore appropriate biomarkers of prognosis in patients with gastric cancer (GC).Material and Methods: All data of patients with gastric cancer were obtained from the database of The Cancer Genome Atlas (TCGA). Samples were divided into two groups based on median TMB. Differently expressed genes (DEGs) between the high- and low-TMB groups were identified and further analyzed. We identified TMB-related genes using Lasso, univariate and multivariate Cox regression analysis and validated the survival result of 11 hub genes using Kaplan-Meier Plotter. In addition, “CIBERSORT” package was utilized to estimate the immune infiltration.Results: Single nucleotide polymorphism (SNP), C > T transition were the most common variant type and single nucleotide variant (SNV), respectively. Patients in the high-TMB group had better survival outcomes than those in the low-TMB group. Besides, eleven TMB-related DEGs were utilized to construct a prognostic model that could be an independent risk factor to predict the prognosis of patients with GC. What’s more, the infiltration levels of CD4+ memory-activated T cells, M0 and M1 macrophages were significantly increased in the high-TMB group compared with the low-TMB group.Conclusions: Herein, we found that patients with high TMB had better survival outcomes in GC. In addition, higher TMB might promote immune infiltration, which could provide new ideas for immunotherapy.

Significance of a preoperative systemic immune-inflammation index as a predictor of postoperative survival outcomes in gastric cancer

BackgroundSince inflammation and the immune system contribute to the development and progression of malignancies, parameters that reflect a host’s immune-inflammatory status may be useful prognostic indicators of gastric cancer (GC). The present study examined the clinical significance of a preoperative systemic immune-inflammation index (SII) for predicting postoperative survival outcomes in GC.MethodsA total of 447 patients who underwent curative gastrectomy for GC were included in the present study. SII was calculated as platelet count × neutrophil count/lymphocyte count. The prognostic impact of preoperative SII was examined using univariate and multivariate analyses.ResultsPreoperative SII ranged between 105 and 4455 (median 474), and the optimal cutoff value for predicting overall survival (OS) was 395 based on a receiver operating characteristic curve. The 5-year OS rate of the SII ≥ 395 group was 80.0%, which was significantly worse than that (92.7%) of the SII < 395 group (p < 0.001). The multivariate analysis identified SII ≥ 395 (hazard ratio [HR] 2.95; 95% confidence interval [CI] 1.49–6.39; p = 0.001), heart disease (HR 2.14, 95% CI 1.07–4.07), C-reactive protein ≥ 0.5 (HR 2.45, 95% CI 1.15–4.94), pT4 (HR 4.46, 95% CI 2.44–8.14), and pN+ (HR 4.02, 95% CI 2.10–7.93) as independent predictors of worse OS. Peritoneal recurrence was more frequent in the high SII group than in the low SII group (p = 0.028).ConclusionPreoperative SII may be a useful predictor of postoperative survival outcomes in GC. The meticulous surveillance of GC relapse, particularly peritoneal dissemination, is necessary for patients with SII ≥ 395 even after curative gastrectomy.

S1370 Real World Survival Outcomes of Gastric Cancer Based on Insurance Status: Evidence From a Large Single Center Study

S1370 Real World Survival Outcomes of Gastric Cancer Based on Insurance Status: Evidence From a Large Single Center Study

Clinicopathological characteristics and survival outcomes of younger patients with gastric cancer: a systematic review and meta-analysis.

BackgroundSurvival outcomes of gastric cancer in younger patients have been reported in several studies with controversial results. This systematic review and meta-analysis investigated the clinicopathological characteristics, postoperative complications, and survival outcomes between younger and older patients.MethodsWe systematically reviewed clinical researches from PubMed, The Cochrane Library, Embase, and Web of science published up to December 2019. The effect size for the included studies was estimated with the odds ratio (OR). Heterogeneity was investigated using the χ2 test and I2 test, while sensitivity analyses were performed to identify the source of substantial heterogeneity.ResultsA total of 25 clinical studies involving 81,188 gastric cancer patients were included in this meta-analysis, of which one was a prospective study. Younger patients were more likely to be females, pTNM stage IV and peritoneal metastasis. The incidence of postoperative complications, lymph node metastasis, as well as hepatic metastasis of younger patients was significantly lower than that of the older. There was no statistical difference in overall survival (OS) between the younger and older patients with gastric cancer. After stratification for patients with gastrectomy, however, younger patients were associated with a better 5-year OS relative to older patients.ConclusionsIn conclusion, younger patients with gastric cancer were more often diagnosed as poorly differentiation and later pTNM tumor stage. However, younger cancer patients following gastrectomy had a better OS rate than patients in older group. Future large-scale analyses are expected to confirm our findings.

Evaluation of Tumor Budding in Predicting Survival for Gastric Carcinoma Patients in Vietnam.

Background:Tumor budding (Bd) has been demonstrated to be a promising prognostic factor in many carcinomas and in gastric cancer. It may represent an optimal additional parameter that is helpful for risk stratification in gastric adenocarcinoma. Hence, the present research was designed to predict the survival outcomes of gastric cancer in Vietnam, applying the tumor budding criteria of the International Tumor Budding Consensus Conference (ITBCC) 2016.Methods:The present study was conducted on 109 gastric cancer patients who underwent surgery but did not receive neo-adjuvant chemotherapy from 2012 to 2015. The patients’ clinicopathological features were recorded. Bd was evaluated according to the 2016 ITBCC criteria and classified as Bd1 (0–4 buds), Bd2 (5–9 buds), and Bd3 (≥10 buds) grades, in addition to being categorized into 2 main Bd groups: low (<10 buds) and high (≥10 buds) Bd. Kaplan–Meier and log-rank models were applied to analyze survival proportions.Results:Of all the patients, 22.9% were classified as Bd1, 31.2% as Bd2, and 45.9% as Bd3 grades. Furthermore, 54.1% patients were categorized into the low and 45.9% into the high Bd groups. Patients with Bd1 and Bd2 grades (the low Bd group) exhibited the best prognosis, with 5-year overall survival (OS) rates of 85.7%, 90.8%, and90.3%, respectively. Patients with Bd3 grade (the high Bd group exhibited the worst prognosis, and none of them lived for 5 years (p < 0.001). Similar to OS rates, disease-free survival (DFS) rates markedly reduced from the Bd1 to Bd3 grade: Bd1, 95.0%; Bd2, 84.7%; and Bd3, 0% (p < 0.001).Conclusion:Patients with different gastric cancer Bd grades exhibited significantly different OS and DFS rates. The present study findings suggest that the ITBCC criteria can be used to stratify Bd for the treatment and prognosis of gastric cancer patients in Vietnam.

Association between MUC5B mutation and prognosis across solid tumors.

e13515 Background: MUC5B encodes Mucin 5B, which is a gel-forming mucin and a major constituent of mucus in the respiratory tract. Previous studies have revealed an increased expression of MUC5B in invasive mucinous adenocarcinoma (IMA) of the lung, indicating it may be involved in the tumorigenesis, and its family member MUC16, which encodes cancer antigen 125 (CA125), a biomarker for tumor diagnosis and the MUC16 mutation was reported to be associated with higher tumor mutation load, and a better survival outcomes in Gastric Cancer. However, the association between MUC5B mutation and prognosis has never been investigated in solid tumors. Methods: Whole-exome sequencing, RNA sequencing and clinical data for 27 types of solid tumors were downloaded from The Cancer Genome Atlas (TCGA). Associations between MUC5B mutation and prognosis were analyzed, and gene set enrichment analysis (GSEA) was used to investigate the underlying mechanism. Results: Among the 27 tumors, MUC5B mutation was associated with a superior disease specific survival (DSS) in Uterine Corpus Endometrial Carcinoma (UCEC) (HR, 0.32; 95% CI, 0.13-0.80; P = 0.01), Bladder Urothelial Carcinoma (BLCA) (HR, 0.43; 95% CI, 0.18-1.05; P = 0.06) and lung adenocarcinoma(LUAD) (HR, 0.44; 95% CI, 0.2-0.95; P = 0.03). MUC5B was also or tended to be associated with longer progression-free survival (PFS) and overall survival (OS) in UCEC (PFS: HR, 0.40; 95% CI, 0.23-0.70; P &lt; 0.001; OS: HR, 0.57, 95% CI 0.31-1.03, P = 0.06), BLCA (PFS: HR, 0.40; 95% CI, 0.19-0.86; P = 0.02; OS: HR 0.42, 95% CI 0.20-0.90, P = 0.02) and LUAD (PFS: HR, 0.63; 95% CI, 0.38-1.06; P = 0.08; OS: HR 0.55, 95% CI 0.31-0.97, P = 0.04). However, MUC5B mutation was associated with poorer OS (HR 1.64, 95% CI 1.03-2.59, P = 0.03) and tended to be associated with poorer PFS (HR 1.56, 95% CI 0.95-2.57, P = 0.08) in Head and Neck squamous cell carcinoma (HNSC). MUC5B mutation was not associated with survival in other tumors. MUC5B mutation was associated with a higher TMB in UCEC, BLCA and LUAD, and GSEA revealed prominent enrichment of signatures related to DNA repair in MUC5B mutation group, compared to MUC5B wide-type group in UCEC (FDR &lt; 0.05), BLCA (FDR &lt; 0.05), and LUAD (FDR &lt; 0.05), but not in HNSC. Conclusions: MUC5B mutation may be a potential predictor for better prognosis in UCEC, BLCA and LUAD, through potentiating DNA damage repair signaling. Identification of MUC5B mutation by genomic profiling provides a potentially novel and convenient approach for these patients to predict the prognosis, and refines patients' management in clinical practice.

Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A systematic review and meta-analysis.

The potential prognostic value of tumor-infiltrating lymphocytes (TILs) in gastric cancer remains controversial. This meta-analysis examines the association between TILs and survival outcomes in gastric cancer. Twenty-two eligible studies were identified using the PubMed and Google Scholar databases. The combined sample size of the 22 studies was 2941, and the median sample size of the individual studies was 122 patients (52-220). The main clinical outcomes examined were overall cancer survival (OCS) and overall cancer relapse-free survival (OCRFS). Tumor tissue CD3(+) TILs, indicative of pan-T-cell expression, had a positive effect on survival with a hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.52-0.78) for OCS, as did the non-FOXP3(+) T-cell subgroup with an HR of 0.66 (95% CI 0.57-0.75), particularly in CD8(+) lymphocytes (HR = 0.63, 95% CI 0.48-0.83). On the contrary, high FOXP3(+) T-cell expression was correlated with reduced OCS, with an HR of 1.75 (95% CI 1.26-2.42). Analysis of the seven studies evaluating OCRFS revealed improved OCRFS with infiltration of non-FOXP3(+) TILs with an HR of 0.59 (95% CI 0.42-0.81) but not FOXP3(+) T lymphocytes with an HR of 1.82 (95% CI 1.30-2.53). The results from this meta-analysis suggest that high expression of TILs, mainly by CD8 lymphocytes, may be a potential prognostic biomarker in patients with gastric cancer.

The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression

ABSTRACTWhether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15–0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoff subset (multivariate Cox: HR 0.41, 95% CI: 0.17–0.96, p = 0.039), in the DDRon subgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06–6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.

An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis.

Some studies have suggested that human epidermal growth factor receptor 2 (HER2) positive is associated with poor outcomes in gastric cancer (GC), whereas another inconsistent studies make the situation confused. This meta-analysis was performed to determine whether HER2 played an independent prognostic role in clinicopathological characteristics and survival outcomes of GC. Combination of GC and human epidermal growth factor 2 or HER2 or HER2/neu or erbB-2 or cerbB-2 or c-erbB2 or CD340 or p185 were used as key words. Data were compared according to the HER2 status. Time-to-event outcomes of overall survival (OS) were analyzed using Hazard Ratios (HRs) with fixed effect, while 5-year survival rate and clinicopathological factors were performed using odd ratios (OR) with random effect. Nighteen trials, from 1986 to October 2013, were identified by two independent authors. A total of 6344 GC patients were included in this meta-analysis, with 1148 HER2 protein overexpression or gene amplification. Comparison of 5-year survival of patients with HER2-positive status versus HER2-negative status showed that OR was 0.58 [95% confidence interval (CI), 0.37-0.91], and the result was significant (P=0.02). The survival outcome of HER2 protein overexpression or gene amplification patients was worse than those with normal HER2 (HR 1.15; 95% CI 1.12-1.18; P<0.00001). However, the difference of III-IV stage ratio between HER2-positive and HER2-negative patients was not significant (OR 1.44; 95% CI 0.95-2.18; P=0.09) even in the subgroup analysis of Asia (P=0.12 and Europe (P=0.51). HER2 protein overexpression or gene amplification in GC patients is associated with a poor survival outcome, and may play a role in GC tumorigenesis.

Prognostic role of tumor-inflating lymphocytes in gastric cancer: A systematic review and meta-analysis.

e15578 Background: Tumor-infiltrating lymphocytes(TILs) may act as major determinants of the host immune response to tumor cells. However, the potential prognostic value of TILs in gastric cancer remains controversial. This meta-analysis analyzed the associations between TILs and survival outcomes in gastric cancer. Methods: Eligible 24 published studies were identified by searching the PubMed and Google scholar databases. The primary clinical outcome was defined as overall survival (OS) or disease-free survival (DFS), which were analyzed by subgroups such as TILs subtype. The total of the study sample sizes in eligible 24 published studies was 3,229, which ranged from 52 to 273 (median, 120) patients. All studies were non-randomized and retrospective study. The only multivariate hazard ratio(HR) among patient survival data were pooled, and pooled multivariate HR with 95% confidence intervals (95% CI) were used to calculate the strength of this association between TILs expression and survival outcome. Results: The pooled multivariate hazard ratios suggested that high expression of TILs was associated with better overall survival outcome (pooled HR = 0.69, 95% CI 0.57–0.82), compared to low TILs expression in twenty-three eligible studies, particularly in CD8(+) lymphocytes (pooled HR = 0.63, 95% CI 0.48 –0.83). In contrast, a pooled analysis of the FOXP3 (+) T cells or Treg subgroup showed that high FOXP3 (+) expression was negatively correlated with OS (pooled HR = 1.88, 95% CI 1.34 –2.63). In an analysis of seven studies on DFS, the infiltration by TILs, CD4(+) or CD8(+) lymphocytes (pooled HR = 0.59, 95% CI 0.42 –0.81), not by the infiltration of FOXP3 (+) T lymphocytes (pooled HR = 1.82, 95% CI 1.30 – 2.53), was significantly associated with better survival outcome. Conclusions: The results from this meta-analysis suggest that TILs and TILs subsets expression can be a potential prognostic biomarker in patients with gastric cancer. Key Words: Tumor-infiltrating lymphocytes, gastric cancer, prognosis, meta-analysis