Single Gastric Cancer Research Articles

Hotspots and trends of risk factors in gastric cancer: A visualization and bibliometric analysis.

The lack of specific symptoms of gastric cancer (GC) causes great challenges in its early diagnosis. Thus it is essential to identify the risk factors for early diagnosis and treatment of GC and to improve the survival rates. To assist physicians in identifying changes in the output of publications and research hotspots related to risk factors for GC, constructing a list of key risk factors, and providing a reference for early identification of patients at high risk for GC. Research articles on risk factors for GC were searched in the Web of Science core collection, and relevant information was extracted after screening. The literature was analyzed using Microsoft Excel 2019, CiteSpace V, and VOSviewer 1.6.18. A total of 2514 papers from 72 countries and 2507 research institutions were retrieved. China (n = 1061), National Cancer Center (n = 138), and Shoichiro Tsugane (n = 36) were the most productive country, institution, or author, respectively. The research hotspots in the study of risk factors for GC are summarized in four areas, namely: Helicobacter pylori (H. pylori) infection, single nucleotide polymorphism, bio-diagnostic markers, and GC risk prediction models. In this study, we found that H. pylori infection is the most significant risk factor for GC; single-nucleotide polymorphism (SNP) is the most dominant genetic factor for GC; bio-diagnostic markers are the most promising diagnostic modality for GC. GC risk prediction models are the latest current research hotspot. We conclude that the most important risk factors for the development of GC are H. pylori infection, SNP, smoking, diet, and alcohol.

Cross-talk of Three Molecular Subtypes of Telomere Maintenance Defines Clinical Characteristics and Tumor Microenvironment in Gastric Cancer.

Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic.

Analysis of Characteristics and Risk Factors of Patients with Single Gastric Cancer and Synchronous Multiple Gastric Cancer among 14,603 Patients.

Synchronous multiple gastric cancer (SMGC) accounts for approximately 6% to 14% of gastric cancer (GC) cases. This study aimed to identify risk factors for SMGC. A total of 14,603 patients diagnosed with GC were prospectively enrolled. Data including age, sex, body mass index, smoking, alcohol consumption, family history, p53 expression, microsatellite instability, cancer classification, lymph node metastasis, and treatment were collected. Risk factors were analyzed using logistic regression analysis between a single GC and SMGC. The incidence of SMGC was 4.04%, and that of early GC (EGC) and advanced GC (AGC) was 5.43% and 3.11%, respectively. Patients with SMGC were older (65.33 years vs 61.75 years, p<0.001) and more likely to be male. Lymph node metastasis was found in 27% of patients with SMGC and 32% of patients with single GC. Multivariate analysis showed that SMGC was associated with sex (male odds ratio [OR], 1.669; 95% confidence interval [CI], 1.223 to 2.278; p=0.001), age (≥65 years OR, 1.532; 95% CI, 1.169 to 2.008; p=0.002), and EGC (OR, 1.929; 95% CI, 1.432 to 2.600; p<0.001). Survival rates were affected by Lauren classification, sex, tumor size, cancer type, distant metastasis, and venous invasion but were not related to the number of GCs. However, the survival rate of AGC with SMGC was very high. SMGC had unique characteristics such as male sex, older age, and EGC, and the survival rate of AGC, in which the intestinal type was much more frequent, was very good (Trial registration number: NCT04973631).

The genetic polymorphisms in the SP4 gene and the risk of gastric cancer.

Aim: Gastric cancer (GC) is the leading cause of cancer death, and is associated withhost genetic factors. This study aimed to determine the impact of SP4 polymorphisms on GC. Materials & methods: Four hundred andeighty-nine GC patients and 481 healthy subjects were recruited. The association between single nucleotide polymorphisms and GC risk was investigated by logistic regression analysis. Results: It was observed that rs39302 and rs7811417 were related to a decreased GC risk. Stratified analyses showed that rs39302 decreased GC susceptibility at ages ≤60years, in men, GC patients who hadpreviously smoked and drank. rs7811417 had a risk-decreasing impact on the patients aged ≤60years, in men, GC patients who were nonsmoking and nondrinking. rs35929923decreased the GC risk of patients in grade III-IV and the lymph node metastasis subgroup. Conclusion: SP4 gene polymorphisms are associated with GC risk.

Deep learning-based AI model for signet-ring cell carcinoma diagnosis and chemotherapy response prediction in gastric cancer.

We aimed to develop a noninvasive artificial intelligence (AI) model to diagnose signet-ring cell carcinoma (SRCC) of gastric cancer (GC) and identify patients with SRCC who could benefit from postoperative chemotherapy based on preoperative contrast-enhanced computed tomography (CT). A total of 855 GC patients with 855 single GCs were included, of which 249 patients were diagnosed as SRCC by histopathologic examinations. The AI model was generated with clinical, handcrafted radiomic, and deep learning features. Model diagnostic performance was measured by area under the receiver operating characteristic curve (AUC), sensitivity, and specificity, while predictive performance was measured by Kaplan-Meier curves. In the test cohort (n=257), the AUC, sensitivity, and specificity of our AI model for diagnosing SRCC were 0.786 (95% CI: 0.721-0.845), 77.3%, and 69.2%, respectively. For the entire cohort, patients with AI-predicted high risk had a significantly shorter median OS compared with those with low risk (median overall survival [OS], 38.8vs. 64.2 months, p=0.009). Importantly, in pathologically confirmed advanced SRCC patients, AI-predicted high-risk status was indicative of a shorter overall survival (median overall survival [OS], 31.0 vs. 54.4 months, p=0.036) and marked chemotherapy resistance, whereas AI-predicted low-risk status had substantial chemotherapy benefit (median OS [without vs. with chemotherapy], 26.0 vs. not reached, p=0.013). The CT-based AI model demonstrated good performance for diagnosing SRCC, stratifying patient prognosis, and predicting chemotherapy responses. Advanced SRCC patients with AI-predicted low-risk status may benefit substantially from adjuvant chemotherapy.

Marital status and survival in patients with gastric cancer.

The objective of this study is to examine the impact of marital status on incidence of metastasis at diagnosis, receipt of surgery, and cause‐specific survival (CSS) in patients with gastric cancer (GC). Research data is extracted from The Surveillance, Epidemiology, and End Results (SEER) database, and 18,196 patients diagnosed with GC from 2004 to 2010 are involved. Effects of marital status on incidence of metastasis at diagnosis, receipt of surgery, and CSS are determined using multivariable logistic regression and multivariable Cox regression models, as appropriate. Single GC patients have a higher incidence of metastasis at diagnosis than married patients, while the differences between divorced/separated patients or widowed patients and married patients are not significant. Among those without distant metastasis, single patients, divorced/separated patients, and widowed patients are much less likely to accept surgery compared with married patients. Finally, in the whole group of 18,196 GC patients, single patients, divorced/separated patients, and widowed patients have shorter CSS compared with married patients, even in each of the TNM stage. Marriage had a protective effect against undertreatment and cause‐specific mortality (CSM) in GC. Spousal support may contribute to higher rate of surgery receipt and better survival in patients with GC.

The accumulation of DNA demethylation in Sat α in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals

Helicobacter pylori (HP) infection is widely recognized as a risk factor for gastric cancer, but only a minority of infected individuals develop gastric cancer. The aim of this study was to determine whether DNA demethylation in non-cancerous gastric mucosa (NGM) significantly enhances susceptibility to gastric cancer. A total of 165 healthy volunteers, including 83 HP-positive and 82-negative individuals, as well as 83 patients with single and 18 with synchronous double gastric cancer (GC) were enrolled in this study. The relative demethylation levels (RDLs) of repetitive sequences, including Alu, LINE-1 and Sat α, were quantified by real-time methylation-specific polymerase chain reaction. The Alu RDL did not exhibit any differences within each respective group, whereas LINE-1 RDL was significantly elevated in cancer tissues compared with the NGM in the other groups (P<0.001). Our results indicated that a gradual increase in Sat α RDL correlated with HP infection and cancer development. Sat α RDL was significantly elevated in the NGM in HP-positive compared with HP-negative (P<0.001), and significantly elevated in cancer tissues (P<0.001). Although the Sat α RDL of the NGM in the total population increased in an age-dependent manner, it was significantly increased in a fraction of younger GC patients (<45 years) compared with all of the others (45 years or older, P=0.0391). In addition, double GC exhibited a significantly higher Sat α RDL in the NGM compared with single GC (P=0.0014). In these two fractions, Sat α RDL in the NGM exhibited an inverse correlation with age. In conclusion, the present study demonstrated that the accumulation of DNA demethylation in Sat α RDL in the NGM with HP infection potentially renders susceptibility to gastric cancer in a fraction of GC patients younger than 45 years or in patients with multiple cancers.

Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect

Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2'-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk.

Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer

Risk factors for gastric cancer (GC) include inter-individual variability in the inflammatory response to Helicobacter pylori infection, in the ability of detoxifying DNA reactive species and repairing DNA damage generated by oxidative stress and dietary carcinogens. To evaluate the association between polymorphic DNA repair genes and GC risk, a case-control study including 314 histologically confirmed GC patients and 548 healthy controls was conducted in a GC high-risk area in Tuscany, Italy. Polymorphic variants of base excision repair (APE1-D148E, XRCC1-R194W, XRCC1-R399Q and OGG1-S326C), nucleotide excision repair (XPC-PAT, XPA-23G>A, ERCC1-19007T>C and XPD-L751Q), recombination (XRCC3-T241M) and alkylation damage reversal (MGMT-L84F) were tested for their potential role in the development of GC by using logistic regression models. The same population was also characterised for GSTT1 and GSTM1 variant alleles to search for possible functional interactions between metabolic and DNA repair genotypes by two-way interactions using multivariate logistic models. No significant association between any single DNA repair genotype and GC risk was detected with a borderline association with the XPC-PAT homozygous genotype [odds ratio (OR) =1.42; 95% confidence interval (CI) 0.94-2.17]. Gene-gene interaction analysis revealed combinations of unfavourable genotypes involving either multiple DNA repair polymorphisms or DNA repair and GST-specific genotypes. The combination of the XPC-PAT and the XPA variant alleles significantly increased GC risk (OR=2.15; 95% CI 1.17-3.93, P=0.0092). A significant interaction was also found between the APE1 wild-type genotype and either the single GSTT1 (OR=4.90; 95% CI 2.38-10.11, P=0.0079) or double GSTM1-GSTT1 null (OR=7.84; 95% CI 3.19-19.22, P=0.0169) genotypes or the XPA-mutant allele (OR=3.56; 95% CI 1.53-8.25, P=0.0012). These findings indicate that a complex interaction between host factors such as oxidative stress, antioxidant capacity and efficiency of multiple DNA repair pathways underlies the inter-individual variability in GC risk.

Abstract 4945: Epigenetic silencing of microRNA-34b/c in human gastric cancer

Abstract Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that some miRNAs are silenced in association with CpG island hypermethylation in cancer. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by 5-aza-2′-deoxycytidine (DAC) and 4-phenylburtyrate (PBA) treatment in GC cell lines. By using miRNA microarray (Agilent technologies), we analyzed a panel of 470 miRNAs in MKN74 and AGS cells treated with or without DAC and PBA, and found that 172 and 151 of the miRNAs were significantly upregulated (&amp;gt;5-fold) by the drug treatment, respectively. Among them, we noted miR-34b and miR-34c, which are direct targets of p53, and are frequently silenced in colorectal cancer. Here, we show that miR-34b and -c are frequently downregulated in GC in association with DNA hypermethylation. Reporter assay revealed strong promoter activity in the upstream CpG island of miR-34b/c. Methylation of the CpG island was frequently observed in GC cell lines (13/13, 100%) and primary GC specimens (83/118, 70%), but not in normal gastric mucosa. By in situ hybridization analysis, we observed downregulated expression of miR-34b in primary GC specimens. Methylation of the CpG island was also detected in the non-tumorous gastric mucosa of the GC patients. Notably, quantitative methylation analysis by bisulfite-pyrosequencing revealed higher methylation levels in gastric mucosa with multiple GCs than those with single GCs. Transfection of precursor molecules of miR-34b or miR-34c into GC cells suppressed cellular growth. Gene expression microarray analysis revealed that miR-34b or miR-34c induced dramatic changes in the gene expression profile in GC cells. Particularly, “cell cycle” and “M phase” genes are significantly enriched among the genes downregulated by miR-34b/c. Our results suggest that miR-34b/c are novel tumor suppressors in GC, and that methylation of miR-34b/c CpG island might be a useful marker to predict GC risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4945.

Possible association between immunocompetence and enhanced risk of multicentric carcinogenesis in both the stomach and other organs in patients with gastric cancer

In a retrospective study, we analyzed the association between the immunocompetence and multicentric carcinogenesis in both the stomach and organs other than the stomach in patients with single gastric cancer (SGC) and those with multiple gastric cancers (MGC). The incidence of primary cancers in other organs in patients with MGC (4/17, 23.5%) was significantly higher than that with SGC (15/202, 7.4%). Our analysis of the immunocompetence revealed a trend towards decreased activity of NK cells and of mitogen-induced blastogenesis in patients with MGC as compared to those with SGC. In patients with SGC, patients with primary cancers in other organs had significantly lower levels of both PHA-induced blastogenesis and CD4/CDs, and revealed a greater trend towards decreased activity of both NK cells and Con A-induced blastogenesis than patients without other primary cancers. These findings may suggest that immunocompetence plays a role in the enhanced multicentric carcinogenesis not only in the stomach but also in cancers of other organs.

Patients with multiple gastric cancers have poorer prognosis than patients with single gastric cancer

The postoperative survival of patients with multiple gastric cancers (MGC) was evaluated in a comparison with that of patients with single gastric cancer (SGC). During the past 30 years, 2,405 patients with gastric cancer underwent gastrectomy in our clinic. Of these patients, 2,241 (93.2%) had SGC and 164 (6.8%) had MGC. The survival of patients With MGC was significantly poorer than that of patients with SGC. The incidence of deaths caused by gastric cancer, by malignancies in organs other than the stomach and by nontumorous diseases other than malignancies was greater in each case in patients with MGC. While, there was no single, independent factor that explained the poorer prognosis of patients with MGC, the significantly greater age of patients with MGC might be responsible for an increased incidence of occurrence not only of other malignancies but also of nontumorous diseases associated with aging.