ELP6 and PLIN5 Mutations Were Probably Prognostic Biomarkers for Patients With Gastric Cancer.

PURPOSE: Gastric cancer (GC) is the fifth leading cancer around world. And prognosis of patients with GC is still undesirable. Our study aimed to explore potential prognostic biomarkers for patients with GC. METHODS: The clinical samples were collected from the Qinghai University Affiliated Hospital, which were subjected to the whole exome sequencing (WES). The other GC-related data were obtained from The Cancer Genome Atlas (TCGA) database. Cross analyses were done to determine the candidate genes. And the final mutated genes were determined by survival analyses, univariate and multivariate Cox regression analyses. CIBERSORT and GSEA were used for immune cell infiltration analysis and functional enrichment, respectively. RESULTS: After cross analyses, 160 candidate-mutated genes were identified. And mutated ELP6 and PLIN5 were significantly independently correlated with the overall survival (OS) of patients with GC. Patients with GC with ELP6 and PLIN5 mutations had worse and better prognosis, respectively. Totally 5 types of immune cells were significantly differentially infiltrated in wild-type and mutated ELP6 and PLIN5 GC samples. In mutated ELP6 and PLIN5 GC samples, totally 7 and 11 pathways were significantly enriched, respectively. CONCLUSIONS: The ELP6 and PLIN5 mutations were probably prognostic biomarkers for patients with GC.

Current status and development trends of morbidity and mortality in gastric cancer patients in Xining, 2009-2016.

OBJECTIVE: The incidence of gastric cancer is declining in parts of Asia including China. This study was designed to investigate the incidence and mortality trend of gastric cancer in different regions and ethnic groups in Xining of Qinghai-Tibet Plateau. METHODS: Data of gastric cancer from January 2009 to December 2016 were collected from Disease Control Center in Xining for repeated cross-sectional study. PRIMARY OUTCOME MEASURES: Gastric cancer. PARTICIPANTS: Xining resident population with pathological diagnosis of gastric cancer. MAIN OUTCOME MEASURE: Age, gender composition ratio, morbidity, mortality and trends. RESULTS: There were 4822 new cases of gastric cancer from 2009 to 2016, including 3583 males and 1239 females; 2290 cases were in villages and 2532 in towns. Male incidence rate (38.37/100,000) was higher than female (13.35/100,000). The incidence in rural areas (39.29/100,000) was higher than in urban areas (20.59/100,000). During 2009-2016, there were 2109 gastric cancer deaths in Xining, 1543 in males and 566 in females. There were 1185 cases in villages and 924 in cities. Male mortality (16.64/100,000) was higher than female (6.42/100,000). The mortality rate in rural areas (20.40/100,000) was higher than in urban areas (7.62/100,000). CONCLUSION: Overall morbidity and mortality rates of gastric cancer are on the rise in Xining. Male morbidity and mortality rates are higher than female ones, and rural areas are higher than urban areas.

Efficacy and Safety of Apatinib for Elderly Patients with Advanced or Metastatic Gastric Cancer After Failure of at Least First-Line Chemotherapy: A Multi-Center, Single-Arm, Phase II Study.

BACKGROUND: Apatinib improves progression-free survival and overall survival with an acceptable safety profile in Chinese patients with chemotherapy-refractory advanced or metastatic gastric cancer. However, the efficacy and safety of apatinib are unclear for elderly patients. This study was undertaken to prospectively investigate the efficacy and safety of apatinib for elderly patients with unresectable advanced or metastatic gastric cancer, who experienced progression to at least one lines of chemotherapy. METHODS: This open-label, single-arm, phase II study enrolled patients aged ≥60 years with advanced gastric cancer, who experienced progression to one or more lines of chemotherapy at five centers in China. Patients received apatinib in an oral dose of 500mg or 250mg daily according to the research physicians' decision. The primary end point was progression-free survival, and the secondary end points were objective response rate, disease control rate, overall survival, and safety. RESULTS: Forty-eight patients were enrolled between June 2017 and September 2019. The median age was 65.5 years (range 60-80 years). Twenty-seven patients (56.3%) started treatment with an initial dose of 500 mg and 21 patients (43.7%) with 250 mg. The median progression-free survival and overall survival were 3.00 months (95% confidence interval, 2.17-3.84) and 8.10 months (95% confidence interval, 4.35-11.85), respectively. The objective response rate and disease control rate assessed by the investigators were 16.7% and 72.9%, respectively. The common side effects were fatigue (58.3%), hypertension (47.9%), abdominal pain (33.3%), proteinuria (29.2%), leukopenia (22.9%), and neutropenia (20.8%). Hypertension (22.9%) was the major grade 3/4 toxicity. CONCLUSION: These data suggest that apatinib is effective and relatively tolerable for elderly patients with unresectable advanced or metastatic gastric cancer who have received at least first-line chemotherapy.

Impact of High Altitude on Clinicopathological Features and Prognosis after R0 Resection for Gastric Cancer: A Population-Based Multicenter Study.

Geographic variation has an important role in both carcinogenesis and prognosis of gastric cancer (GC). High altitude is a special hypoxic environment that is also correlated with the occurrence of GC. Different onset features and prognoses of GC in high altitude with respect to plains are rarely reported and remain unknown. This multicenter study compared different clinicopathological characteristics and prognoses of patients with resected GC who were from locations of both high altitudes and plains in China. From December 2009 to December 2011, patients with resected GC were retrospectively recruited at four centers located at high altitudes and the plains. Clinicopathological data were analyzed to explore the differences between the two groups. The Cox proportional-hazards model was used to investigate the prognostic factors for GC and estimate the independent impact of altitude on long-term survival after adjusting for covariates. Noncardia GC, from a moderate to well tumor grade, was more common in patients from high altitudes. Moreover, a higher proportion of moderate to well and moderate tumor grade and younger age of onset was found in patients with noncardia GC coming from high altitudes. Different overall survival (OS) presented in noncardia GC rather than cardia GC, with 69.94% GC-related 3-yr OS in high altitude versus 75.23% in the plains. High altitude was confirmed as a significant prognostic factor for noncardia GC (the hazard ratio for high altitude vs. plains was 1:50, with a 95% confidence interval; 1.06-1.82, p = 0.018) through a multivariate Cox proportional-hazards model analysis. This prognostic value was independent of all other factors. High altitude has an important role in clinicopathological features and prognosis of GC. Improvements in GC diagnosis and management at high altitudes are urgently needed.

Impact on long-term survival of the number of lymph nodes resected in patients with pT1N0 gastric cancer after R0 resection: A multicenter study in China.

Although studies on the association between the number of lymph nodes resected and prognosis in patients with pT2-4N0 stages of gastric cancer have reported consistent results, there is no consensus on the optimal number of lymph nodes to be examined for pT1N0 stage gastric cancer. The aim of this study was to evaluate the long-term effect of the number of lymph nodes removed on the outcomes of patients with pT1N0 stage gastric cancer after R0 resection.From December 2009 to December 2011, 227 patients undergoing R0 resection of pT1N0 stage gastric cancer at 4 Chinese centers were enrolled in this study. Patients were assigned to 2 groups according to the number of lymph nodes dissected (≤15 or > 15). Standard survival methods and restricted multivariable Cox regression models were applied.More women (P = 0.031) were in the ≤15 group than in the >15 group. The mean number of lymph nodes removed from women was greater than that from men (P = 0.007). The 5-year survival rate was significantly higher in the >15 lymph nodes resected group than the ≤15 group. The number of lymph nodes resected was identified as an independent prognostic factor and was significantly correlated with overall survival (OS).A lymphadenectomy with dissection of more than 15 lymph nodes improved the long-term survival of patients with pT1N0 gastric cancer after R0 resection. Therefore, it is necessary to consider removing more than 15 lymph nodes among such patients.

Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China.

AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection. METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors. RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival. CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population.

Cardia and Non-Cardia Gastric Cancer Have Similar Stage-for-Stage Prognoses After R0 Resection: a Large-Scale, Multicenter Study in China.

Although the clinicopathological features of cardia gastric cancer (GC) differ from those of non-cardia GC, it is unclear whether the former has poorer prognosis than the latter. The aim of this study was to compare clinicopathological characteristics and prognosis between cardia and non-cardia GC. From December 2009 to December 2011, 1633 patients who had undergone R0 resection of GC at four Chinese centers were enrolled in this study. Their clinicopathological features and survival outcomes were evaluated. Compared with non-cardia GC, cardia GC was associated with a significantly higher proportion of male patients, older age, more advanced pathological stage, and less-favorable clinicopathological features at diagnosis. The 5-year survival rate was significantly lower in the cardia GC group than in the non-cardia GC group. However, no significant difference in overall survival (OS) was observed between the two groups at any pathological TNM stage. Pathological stage was confirmed as an independent prognostic factor of OS. More advanced disease represents most of the cases in this Chinese population. Compared with patients with non-cardia GC, patients with cardia GC were diagnosed at a more advanced stage and had worse prognosis after undergoing R0 resection. However, cardia and non-cardia GCs have similar stage-for-stage prognoses.

Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell.

EPAS-1/HIF-2α (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2α) is a transcription factor expressed in a wide range of human cancers, including stomach cancer. Although EPAS-1 has been studied for years, its function in oncogenic transformation processes needs to be further investigated. In this study, we found that EPAS-1 would promote the growth of stomach cancer cell line BGC-823. Our results revealed that EPAS-1 interacts with Pregnane X Receptor (PXR), a nuclear receptor that regulates multiple genes' transcription involved in multi-drugs resistance (MDR) process. Protein-protein interaction between EPAS-1 and PXR was identified by co-immunoprecipitation and GST-pull down assays. By this interaction, EPAS-1 recruited PXR to its response elements in promoter/enhancer regions of CYP3A4, a PXR target gene. Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel. Reduction of EPAS-1 level via its siRNA disrupted the proliferation, and enhanced the susceptibility of BGC-823 cells to those chemotherapeutic drugs. Our findings suggested that EPAS-1 and PXR may cooperatively participate in development and especially MDR process of stomach cancer. These findings may contribute to more effective targeted drugs discovery for the stomach cancer therapy.

Prostate stem cell antigen rs2294008 polymorphism differentially contributes to Helicobacter pylori-negative gastric cancer among various populations in China.

Gastric cancer is a lethal disease with a high mortality rate. Studies have suggested that prostate stem cell antigen (PSCA) rs2294008 polymorphism is associated with gastric cancer (GC). In this case-control study, we investigated rs2294008 polymorphism in the Tibet, Hui and Han nationalities in the Qinghai area of China. Genomic DNA was extracted from the peripheral blood of 286, 315 and 350 healthy volunteers and from 219, 233 and 265 Helicobacter pylori-negative non-cardia GC patients from the Tibet, Hui and Han populations, respectively. The rs2294008 polymorphism was analyzed by denaturing high-performance liquid chromatography. rs2294008 CT and TT genotypes were associated with GC both in the Tibet and Han populations (adjusted OR=1.51, 1.47, 2.01, 1.85; 95% CI, 1.04-2.19, 1.05-2.06, 1.04-3.88, 1.03-3.34; P=0.030, 0.025, 0.039, 0.040, respectively). rs2294008 TT genotype was associated with GC in the Hui population (adjusted OR=2.14; 95% CI, 1.29-3.55; P=0.003). Furthermore, when stratified by histopathology, the rs2294008 CT and TT genotypes were associated with diffuse GC in the Tibet and Han nationalities (adjusted OR=1.93, 1.73, 2.69, 2.86; 95% CI, 1.09-3.44, 1.01-2.95, 1.06-6.84, 1.27-6.46; P=0.025, 0.045, 0.038, 0.011, respectively). However, the rs2294008 TT genotype was associated with both intestinal and diffuse types of GC (adjusted OR=2.10, 2.21; 95% CI, 1.17-3.75, 1.12-4.38; P=0.012, 0.023, respectively) and the rs2294008 CT genotype was only associated with intestinal-type GC in the Hui nationalitiy group (adjusted OR=1.60; 95% CI, 1.04-2.47; P=0.034). The results therefore showed that rs2294008 may differentially contribute to GC among different nationalities in one area and its role is independent from Helicobacter pylori-infection.

Associations between interleukin-1 polymorphisms and gastric cancers among three ethnicities.

AIM: To investigate the associations between interleukin (IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet, Hui and Han ethnicities. METHODS: Genomic DNA was extracted from peripheral blood of 210, 205, and 202 healthy volunteers and from 155, 158, and 197 gastric cancer patients from the Tibet, Hui, and Han populations, respectively. Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography. RESULTS: Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio (OR) = 2.17, P = 0.037] in the Tibet ethnicity. Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer (OR = 2.08, 2.31, P = 0.007, 0.016, respectively) in the Hui ethnicity. In the Han population, carriers of the IL-1B-31 CC, IL-1B-511CT, TT genotypes had increased risk of intestinal type gastric cancer (OR = 2.51, 2.74, 5.66, P = 0.005, 0.002, 0.000, respectively). CONCLUSION: IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet, Hui, and Han ethnicities in the Qinghai area of China.