Primary Gastric Cancer Research Articles

Gastric Remnant Cancer: Complete Pathological Response - Case report

Background: Remnant gastric cancer (RGC) refers to carcinoma of the residual stomach occurring after gastrectomy. With an incidence of 1-7%, it is believed to have a different disease mechanism and a poorer prognosis than primary gastric cancer (PGC). However, due tu its rarity, the standard treatment for RGC remains undefined. Therefore, the multidisciplinary/tailored approach becomes crucial for the treatment of these patients.

Proposal of modified textbook outcome for improving the quality of gastric cancer surgery: A single-center study.

270 Background: Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Since 2014, the national healthcare quality assessment has been implemented for gastric cancer in Korea, which has the highest incidence. The proportion of early gastric cancer through early detection is high in Korea, and gastric cancer surgery has a great influence on outcome index. The aim of this study is to find indicators that can improve Textbook outcome (TO) in patients undergoing gastric cancer surgery. Comparing with Western data, we intended to propose a modified TO (mTO). Methods: Using a prospective clinical database, we included consecutive cases of gastrectomy for primary gastric cancer between 2014 and 2016. TO was achieved when 10 original indicators proposed by the DUCA group were satisfied. We propose to adjust the index of the number of retrieved lymph nodes from 15 to 30 as the modified TO(mTO) indicator for improving the quality of gastrectomy. For comparison with Western data, we calculated TO, mTO and survival in stage I versus Stage II and III. Results: A total of 2,153 patients were included. TO was achieved in 80.1 percents by 10 original indicators. Most of the indicators showed more than 90 percents of TO satisfaction. Five-year survival was significantly different between the TO (90.0%) and non-TO (76.1%) groups ( P < 0.001). For 608 patients in stage II and III, TO was 72.9 percents, which was much higher than the Western publications. Five-year survival were 74.8 percents for the TO group and 56.8 percents for the non-TO group in stage II and III patients. We found that the number of metastatic lymph nodes increases as the stage increases and even the number of metastatic lymph nodes in stage IIIC exceeded 19. The modified textbook outcome (mTO) for stage II and III was 65.3 percents, and five–year survival was significantly different between mTO (74.0%) and mnon-TO (62.1%) groups ( P < 0.001). To prevent R1 resection and minimize the proportion of remnant total gastrectomy, we performed frozen study examinations of the proximal and distal margins as to ensure high oncological safety. Conclusions: Data from a high volume gastric cancer center showed the high textbook outcome rates. It suggests that the minimum number of lymph node retrievals should be at least 30, even in advanced gastric cancer, and routine intraoperative frozen study examination are necessary to increase R0 resection.

Dual-Aptamer-Targeted Immunomagnetic Nanoparticles to Accurately Explore the Correlations between Circulating Tumor Cells and Gastric Cancer.

It has been acknowledged that circulating tumor cells (CTCs) are promising biomarkers in liquid biopsy for cancer diagnosis and prognosis. However, the relationship between the CTC number and gastric cancer has scarcely been quantitatively investigated. Moreover, the single criterion of epithelial cell adhesion molecule (EpCAM) antibody/aptamer to specifically recognize epithelial CTCs cannot be universally applied for clinical applications, as it fails to recognize EpCAM-negative CTCs. Herein, we propose simple, low-cost, dual-aptamer (EpCAM and PTK7)-modified immunomagnetic Fe3O4 particles (IMNs) for efficient capture of heterogeneous CTCs and downstream analysis in gastric cancer patients. High PTK7 expression and a significant negative correlation between PTK7 and EpCAM expression were observed in primary gastric cancer tissues. Taking MGC-803 and BGC-823 cells as CTC models, the obtained dual-targeting IMNs could distinguishably recognize these cells with both high or low EpCAM and PTK7 expressions, which enhanced the accuracy of CTC recognition in gastric cancer. More than 95% of these two kinds of cells could be captured within 20 min of incubation, which was significantly more efficient than that of single EpCAM- or PTK7-modified IMNs. With this strategy, as low as five CTCs could be captured from phosphate-buffered saline (PBS), a cell mixture containing THP-1 cells, and lysed blood mediums. Moreover, the obtained CTCs can be used for subsequent gene analysis. Finally, the fabricated IMNs were successfully applied for CTC capture in 1.0 mL of peripheral blood samples from patients with gastric cancer. The detected CTC numbers in 72 participants were found to have close relationships with chemotherapy sensitivity, diagnosis, stage, and distant metastasis of patients. This work provides important references for further investigations on CTC-related diagnosis and individualized treatment.

Association of an immunosuppressive macrophage transcriptional signature derived from peripheral blood macrophages with gastric cancer prognosis.

354 Background: Gastric cancer (GC) is the fourth most common cause of cancer death worldwide. Studies have shown an association of higher macrophage density in the tumor microenvironment with worse outcomes in GC. The presence of M2 specific gene signatures in the peripheral blood of cancer patients are associated with poor prognosis. However, it is unknown whether these immunosuppressive M2 markers are prognostic when found in the primary GC tumors. Methods: Based on previously published differential gene expression profiles that distinguish M1 versus M2 macrophages in the peripheral blood, we used the UCSC Xena webtool to analyze the TCGA Stomach Cancer cohort for tumor-associated immune signatures for their prognostic value. We excluded null entries, normal tissue, and entries with incomplete data. We investigated both M1- and M2-macrophage signatures (M1 signature: CCR7, IL2RA, CXCL11, CCL19, CXCL10, PLA1A, PTX3 and M2 signature: MRC1, MS4A4A, CD36, CCL13, CCL18, CCL23, SLC38A6, FGL2, FN1, MAF); as well as a T cell cytolytic signature defined by genes with cytolytic functions ( GZMA, GZMB, GZMH, GZMM, PRF1). We analyzed the impact of transcriptional gene expression with relation to stage, histological subtype, overall survival (OS), and disease free interval (DFI). The UCSC Xena webtool uses log-rank test to compare Kaplan-Meier curves. Results: A total of 341 entries were analyzed with age ranging from 30-90 and 39.4% female. Increased CD168 expression was associated with increased stage of GC (p = 0.017). Higher expression of the M2-macrophage signature was associated with diffuse type adenocarcinoma and mucinous type intestinal adenocarcinoma, compared to tubular and papillary type intestinal adenocarcinoma (p < 0.001). In addition, higher M2-macrophage signature expression was associated with late stage (Stage II or above) compared to early stage (stage I) (p = 0.022). A low M2-macrophage signature was associated with improved 5-year OS (p = 0.029), and a significantly improved 5-year DFI (p = 0.042). CD8A, cytolytic T cell signature, and M1 macrophage signature were not associated with stage of disease or survival. Conclusions: A transcriptional signature derived from peripheral blood immunosuppressive M2 macrophage phenotype is found in GC primary tumors and associated with higher pathologic staging and with worse outcomes. These M2 defining molecular biomarkers of GC has the potential to serve as targets of novel immune-therapeutic strategies.

A nomogram for predicting lymph node metastasis in early gastric cancer

Objective: To explore the independent risk factors of lymph node metastasis (LNM) in early gastric cancer, and to use nomogram to construct a prediction model for above LNM. Methods: A retrospective cohort study was conducted. Inclusion criteria: (1) primary early gastric cancer as stage pT1 confirmed by postoperative pathology; (2) complete clinicopathological data. Exclusion criteria: (1) patients with advanced gastric cancer, stump gastric cancer or history of gastrectomy; (2) early gastric cancer patients confirmed by pathology after neoadjuvant chemotherapy; (3) other types of gastric tumors, such as lymphoma, neuroendocrine tumor, stromal tumor, etc.; (4) primary tumors of other organs with gastric metastasis. According to the above criteria, 1633 patients with early gastric cancer who underwent radical gastrectomy at the Department of General Surgery of the Chinese PLA General Hospital First Medical Center from December 2005 to December 2020 were enrolled as training set, meanwhile 239 patients with early gastric cancer who underwent gastrectomy at the Department of General Surgery of the Chinese PLA General Hospital Fourth Medical Center from December 2015 to December 2020 were enrolled as external validation set. Risk factors of LNM in early gastric cancer were identified by using univariate and multivariate logistic regression analyses. A nomogram prediction model was established with significant factors screened by multivariate analysis. Area under the receiver operating characteristic curve (AUC) was used for assessing the predictive value of the model. Calibration curve was drawn for external validation. Results: Among 1633 patients in training set, the mean number of retrieved lymph nodes was 20 (13-28), and 209 patients (12.8%) had lymph node metastasis. Univariate analysis showed that gender, resection range, tumor location, tumor morphology, lymph node clearance, vascular invasion, lymphatic cancer thrombus, tumor length, tumor differentiation, microscopic presence of signet ring cells and depth of tumor invasion were associated with LNM (all P<0.05). Multivariate analysis revealed that females, tumor morphology as ulcer type, vascular invasion, lymphatic cancer thrombus, tumor length≥3 cm, deeper invasion of mucosa, and poor differentiation were independent risk factors for LNM in early gastric cancers (all P<0.05). Receiver operating characteristic curve indicated that AUC of training set was 0.818 (95%CI: 0.790-0.847) and AUC of external validation set was 0.765 (95%CI: 0.688-0.843). The calibration curve showed that the LNM probability predicted by nomogram was consistent with the actual situation (C-index: 0.818 in training set and 0.765 in external validation set). Conclusions: Females, tumor morphology as ulcer type, vascular invasion, lymphatic cancer thrombus, tumor length≥3 cm, deeper invasion of mucosa and poor differentiation are independent risk factors for LNM of early gastric cancer. The establishment of a nomogram prediction model for LNM in early gastric cancer has great diagnostic value and can provide reference for treatment selection.

Detection of secondary upper gastrointestinal tract cancer during follow-up esophagogastroduodenoscopy after gastrectomy for gastric cancer.

AimEsophagogastroduodenoscopy (EGD) may contribute to early detection of secondary cancer in the upper gastrointestinal tract although the clinical relevance of follow‐up after gastrectomy remains unclear. This study aimed to elucidate the effectiveness of follow‐up EGD by investigating the incidence of secondary cancer in any part of the upper gastrointestinal tract.MethodsData from 1438 patients who underwent curative partial gastrectomy for primary gastric cancer between 2008 and 2014 and follow‐up EGD at least once during a 5‐year follow‐up period were retrospectively reviewed. Incidence rates of remnant gastric cancer, laryngeal cancer, and esophageal cancer detected after follow‐up EGD were determined, and risk factors for secondary cancers were examined. The characteristics of clinicopathological diagnoses of secondary cancers were reviewed and compared according to the frequency of follow‐up EGD.ResultsThe average annual frequency of EGD was 0.7, while the 5‐year cumulative incidence rates of remnant gastric cancer and secondary laryngeal and esophageal cancers were 2.9% and 1.3%, respectively. Risk factors for remnant gastric cancer included heavy smoking, proximal gastrectomy, and tumor size ≥ 30 mm. All secondary cancers were resectable upon diagnosis, with endoscopically resectable cancer accounting for 81.0% of cases. Our results found a significantly higher proportion of endoscopically resectable cancers during regular follow‐up than during infrequent follow‐up.ConclusionsFollow‐up EGD can be a useful modality for detecting secondary upper gastrointestinal tract cancer, likely leading to curative treatment for secondary cancer. Focusing on patients presenting with risk factors may increase the value of follow‐up EGD after gastrectomy.

Case\u2013control study on TP73 rs1801173 C\u2009>\u2009T gene polymorphism and susceptibility to gastric cancer in a Chinese Han population

BackgroundThis study investigated the role of TP73 gene polymorphism, rs1801173on risk of gastric cancer.MethodsWe conducted a case-controlled study including 577 primary gastric cancer and 678 normal control cases. The target gene fragment was amplified using PCR using blood samples collected from patients. Allele analysis and genotyping were performed using snapshot method.ResultsThe findings showed that the control group had consistent genotype frequency distribution and presented Hardy–Weinberg equilibrium. The results showed no significant differences in sex, drinking history and age distributions between subjects with the polymorphism and subjects in the control group. Smoking status was correlated with incidence of gastric cancer (P = 0.006). The rs1801173 locus of TP73 gene contained 3 genotypes including: TT, CT, and CT. Logistic regression analysis showed that distribution of recessive model and dominant model was comparable between the two groups before (P = 0.688; 0.937) or after (P = 0.703; 0.990) adjusting for confounders. The distribution frequency in case group was not significantly different relative to that of the control group (P = 0.763).ConclusionSmoking can independently influence the risk of gastric cancer. TP73 gene rs1801173 polymorphism was not significantly correlated with risk of gastric cancer.

Risk and Prognosis of Subsequent Primary Gastric Cancer

Introduction: The incidence and prognostic impact of subsequent primary gastric cancer (GC) in a population of other cancer survivors is unclear. We aimed to evaluate susceptibility to subsequent primary GC in cancer survivors and prognosis of GC with prior cancer history. Methods: A total of 2,211 and 23,416 GC cases with and without prior cancer history were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database. Potential risk of developing subsequent primary GC was assessed through standardized incidence ratios (SIRs). Cox regression was adopted to analyze the influence of prior cancer history and clinical characteristic factors on the prognosis of subsequent primary GC. A nomogram was established to predict overall survival (OS). Propensity score matching was conducted to eliminate possible bias. Results: Compared with general population, cancer survivors had an increased risk of subsequent primary GC (SIR 1.17, 95% CI: 1.15–1.20, p < 0.05). Prior cancer history was related to poor OS of GC (adjusted hazard ratio [aHR] 1.12, 95% CI: 1.06–1.19, p < 0.001), but not cancer-specific survival (aHR 0.97, 95% CI: 0.89–1.05, p = 0.441). In addition, age, grade, stage, year of diagnosis, surgery, TNM stage, and tumor size were independent prognostic factors for OS in GC cases with prior cancers. The concordance index of the nomogram was 0.72 (95% CI: 0.71–0.74), and calibrate curves showed good agreement between prediction by the nomogram and actual observation. Conclusions: Cancer survivors with increased risk of developing subsequent primary GC should strengthen their monitoring and follow-up to prevent occurrence of subsequent primary GC.

The Application Value of ceMDCT in the Diagnosis of Gastric Cancer Extramural Vascular Invasion and Its Influencing Factors.

Objective To investigate the value of enhanced multislice spiral CT (ceMDCT) in the diagnosis of extramural vascular invasion of gastric cancer and the influencing factors of extramural vascular invasion. There are different methods used in this paper. Method 131 patients with primary gastric cancer treated in our hospital from January 2017 to May 2019 were selected. All patients underwent surgical resection and ceMDCT examination before operation. Result There were 40 cases with extramural vascular invasion of gastric cancer by surgical pathological diagnosis. The kappa value of ceMDCT in diagnosing extramural vascular invasion of gastric cancer was 0.947, and the consistency was excellent. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were 100.00%, 96.70%, 93.02%, and 100.00%, respectively. The proportions of T3-T4, tumour diameter ≥5.0 cm, and growth pattern of proximal nodular + diffuse type in patients with gastric cancer extramural vascular invasion were 92.50%, 85.00%, and 65.00%, respectively, which were significantly higher than those in patients without extramural vascular invasion (P < 0.05). The logistic regression analysis results showed that T3-T4, tumour diameter ≥5.0 cm, proximal nodular + diffuse growth pattern were the risk factors for extrahepatic vascular invasion in gastric cancer (OR = 3.751, 2.901, and 3.367, P < 0.05). Conclusion ceMDCT has good application value in diagnosing gastric cancer extramural vascular invasion. The occurrence of gastric cancer extramural vascular invasion is affected by T staging, tumour diameter, and tumour growth pattern.

Gastrin/CCK-B Receptor Signaling Promotes Cell Invasion and Metastasis by Upregulating MMP-2 and VEGF Expression in Gastric Cancer.

Accumulated evidence suggests that a functional loop composed of gastrin and cholecystokinin B receptor (CCK-BR) may exist in gastric carcinogenesis. However, this suggestion is not completely supported due to a lack of direct evidence, and the underlying mechanism is not completely understood. Here, we evaluated the effects of gastrin/CCK-BR signaling on the cell growth, invasion, and expression of MMP-2 and VEGF, as well as xenograft growth in vivo. Furthermore, we detected gastrin mRNA content in human gastric cancer tissues, metastatic lymph nodes, and adjacent nontumor tissues. We found that the forced gastrin could promote the proliferation, migration, and invasion of gastric cancer cells by upregulating the expression of MMP-2 and VEGF. Blocking gastrin/CCK-BR signal using either Proglumide, a CCK-BR antagonist, or shRNA against GASTRIN significantly inhibited the gastrin-promoting effects. In vivo study revealed that the tumor growth in nude mice inoculated with gastrin-overexpressed cells was significantly faster than control cells. The gastrin mRNA content in metastatic lymph nodes was higher in patients with gastric cancer than in primary gastric cancer and adjacent nontumor tissues. In conclusion, we provided direct evidence and possible mechanism of gastrin/CCK-BR signaling in the initiation and progression of gastric cancer.

Cautions should be taken when using cell models for gastric cancer research.

Gastric cancer (GC)-derived cell lines were generally used in basic cancer research and drug screening. However, it is always concerned about the difference between cultured cells and primary tumor by oncologists. To address this question, we compared differentially expressed genes (DEGs) in primary cancers, healthy tissues, and cell lines both in vitro and in silico. Seven reported genes with decreased expression in GCs by DNA methylation were analyzed in our cohort studies and experimentally validation. Selected datasets from TCGA (The Cancer Genome Atlas), CCLE (The Broad Institute Cancer Cell Line Encyclopedia), and GTEx (The Genotype-Tissue Expression project) were used to represent GCs, GC-derived cell lines, and healthy tissues respectively in the in silico analysis. Thirty gastric tissues together with six cell lines were used for validations. Unexpectedly, we experimentally found that reported cancer-related downregulated genes were only found in cancer cell lines but not in biopsies. The unchanged gene expressions in primary GCs were generally consistent with our cohort study, using information from cancerous (TCGA) and healthy tissues (GETx). Substantial differences were also found between DEGs of cancer tissues (TGCA)/ healthy tissues (GTEx) pair and cell lines (CCLE)/ healthy tissues (GTEx) pair, which confirmed the significant differences between primary cancer and cancer cell lines. Moreover, elevated expression of YWHAQ (14-3-3 δ) and THBS1 were observed in the GC biopsies, which might be potential biomarkers for GC diagnosis, considering the increased YWHAQ and THBS1 associated with poor survival rates in gastric cancer patients. In sum, it is suggested that cautions should be taken when using GC cell lines to study genes that show great differences between cell lines and tissues.

Totally laparoscopic total gastrectomy using the "enjoyable space" approach coupled with self-pulling and latter transection reconstruction versus laparoscopic-assisted total gastrectomy for upper gastric cancer: short-term outcomes.

IntroductionWith the development of minimally invasive surgery in recent years, totally laparoscopic total gastrectomy (TLTG) has attracted more attention.AimTo introduce the more comprehensive “enjoyable space” approach coupled with the self-pulling and latter transaction (SPLT) reconstruction technique to perform TLTG and investigate its safety and feasibility.Material and methodsNinety-seven patients with primary upper gastric cancer underwent laparoscopic radical total gastrectomy between January 2020 and December 2020. Among these patients, 46 underwent laparoscopic-assisted total gastrectomy (LATG), and 51 underwent TLTG. We compared the clinicopathological characteristics, surgical outcomes and postoperative complications between the two groups.ResultsThere were no significant differences in the clinicopathological characteristics between the two groups (p > 0.05). However, the TLTG group had a slightly lower mean operative time and mean blood loss than the LATG group (p < 0.05 each). Although there were similarities in the mean times to first flatus, liquid diet, and soft diet, the duration of hospital stay was significantly reduced in the TLTG group (p < 0.05). No significant differences in overall complications and E-J-related complications were found between the two groups (15.2% vs. 25.4%, p > 0.05).ConclusionsTLTG is a safe and feasible procedure for treating upper gastric cancer. The enjoyable space approach in conjunction with SPLT reconstruction is an appropriate comprehensive technique with several advantages over LATG.

The Clinical Impact of Synchronous and Metachronous Other Primary Cancer in Gastric Cancer Patients Who Receive Curative Treatment.

The present study evaluated the clinical characteristics and prognostic factors of gastric cancer (GC) patients with synchronous and metachronous other primary cancer who received curative treatment for GC. The study included 244 patients who underwent curative treatment for GC between 2005 and 2018. The risk factors for the overall survival (OS) and recurrence-free survival (RFS) were identified. A total of 244 patients were included in this study. Among them, 58 patients were diagnosed with synchronous and metachronous other primary cancer. When comparing the patient background characteristics and clinical course between GC patients without and with synchronous and metachronous other primary cancer, the background, postoperative surgical complications, and details of adjuvant treatment were similar between the two groups. The 3- and 5-year OS rates in GC patients with synchronous and metachronous other primary cancer were 69.7% and 48.0%, respectively, while those in patients without synchronous and metachronous other primary cancer were 80.6% and 74.3%, respectively, showing a statistically significant difference (p<0.001) The synchronous and metachronous other primary cancer status was included in the final multivariate analysis model (hazard ratio=2.201; 95% confidence interval=1.229-3.942; p=0.008). Synchronous and metachronous other primary cancer status is a prognostic factor in GC patients. Therefore, synchronous and metachronous other primary cancer patients need both other primary cancer and GC follow-up to improve their survival.

Primary gastric choriocarcinoma: a rare and aggressive gastrointestinal malignancy.

A 40-year-old male with no previous medical history presented to emergency department with a 2-week history of progressive dyspnea. He also described night sweats and weight loss (15 kg) during the last 3 months. Thoraco-abdominal computed tomography showed multiple bilateral lung nodules associated with supra-clavicular, hilar and peri-esophageal lymphadenopathies and gastric parietal thickening. These imaging features were suggestive of primary gastric cancer with lung and lymph node metastases. Therefore, he undergone upper digestive endoscopy that showed a large ulcerated protruding lesion at the greater curvature of the body suggestive of malignancy. Gastric biopsies of the lesion confirmed a solid neoplasia constituted by solid nests and sheets of highly pleomorphic, bizarre cells with cytotrophoblastic and syncytiotrophoblastic differentiation that, on immunohistochemistry, stained positive for β-HCG, SALL-4 and glypican-3. CT-guided biopsy of lung nodules revealed malignant cells with similar histopathological and immunohistochemical features. Elevated serum alpha-fetoprotein and β-HCG were also detected. Clinical and ultrasound examination were negative for testicular masses. These findings were consistent with a primary gastric choriocarcinoma presenting with lung and lymph node metastases (stage IV). Although chemotherapy was started, the patient evolved unfavorably and died after 9 months. Primary gastric choriocarcinoma is a rare and aggressive gastrointestinal malignancy. This case demonstrates its rapid growth rate and high metastatic potential that may lead to symptoms from secondary involvement of distant organs.

Current Evidence for a Paradigm Shift in Gastric Cancer Prevention From Endoscopic Screening to Helicobacter pylori Eradication in Korea.

Gastric cancer is prevalent in Korea and ranked as the third most common cancer in 2019, followed by lung and thyroid cancers. The National Cancer Screening Program (NCSP) for gastric cancer has been implemented in adults aged ≥40 since 1999 and involves endoscopic screening every 2 years. The beneficial effects of the current NCSP on early cancer detection, cost-effectiveness, and mortality reduction are evident. However, the screening program results in a large socioeconomic burden and the consumption of medical resources, as it focuses solely on secondary prevention (early detection) rather than primary prevention of cancer. Helicobacter pylori is defined as a group I carcinogen by the International Agency for Research on Cancer. Hence, its eradication has been suggested as an important primary gastric cancer prevention strategy. Well-designed randomized controlled trials involving high-risk groups (post-endoscopic resection of early gastric cancer and family history of gastric cancer) and long-term follow-up studies in the general population have provided high-quality evidence regarding the effects of H. pylori eradication on gastric cancer prevention. In this review, we discussed the evidences for a possible modification of the current gastric cancer secondary prevention strategy by introducing primary prevention through H. pylori eradication. Areas for future research to optimize primary prevention strategies were also suggested.

The functional variant in promoter of OVCA1 was associated with the risk of gastric cancer in the northeast Chinese Han population

We previously found allelic deletions on chromosomes 17 in primary gastric cancers (GC) using microsatellite markers for loss of heterozygosity (LOH). OVCA1 lies in one of these regions (17q21.33). The association between single nucleotide polymorphism (SNP) of OVCA1 gene and risk of gastric cancer is not yet clear. In this study, the peripheral blood of 505 gastric cancer patients and 544 healthy controls were genotyped for six SNPs (rs2273981, rs1131600, rs3752963, rs3803806, rs2236375, and rs1051322) of OVCA1, to evaluate the association of these SNPs with the risk of gastric cancer in the Han population in northeast China. The effect of rs2273981 located in the promoter region of OVCA1 on the transcription activity was determined using dual luciferase reporter assay. We found that the association between the AA + AG genotype of rs2273981 and the risk of gastric cancer was significant in smokers (AA + AG vs. GG, OR = 2.47, 95% CI = 1.04 – 5.87, P < 0.05). Stratified analysis of the clinicopathological parameters revealed that rs1131600 AG + GG genotype were significantly associated with increased gastric tumor volume (AG + GG vs. AA, OR = 1.81, 95% CI = 1.00 – 3.29, P < 0.05). The rs2236375 CT + TT genotype was also significantly associated with increased gastric tumor volume (CT + TT vs. CC, OR = 2.65, 95% CI = 1.38 – 5.10, P < 0.05). Additionally, by interacting with the transcription factor AP2A, the GG genotype the rs2273981 increased the transcription activity of OVCA1 compared with AA genotype, thus involved in gastric cancer development.

Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis.

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p

BackgroundDysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer.MethodsA circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays.ResultscircDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy.ConclusionsOverall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.

Location Matters: Profiling Diffuse Type Gastric Cancer At the Single-Cell Level.

Spatial single-cell transcriptomics of primary patient diffuse type gastric cancer reveals distinct cancer and stromal cell differences based on location. Expression of CCL2 by stromal cells in deep tumor regions is highlighted as potentially driving the immunosuppressive microenvironment and enhancing (directly or indirectly) the invasive capacity of tumor cells.See related article by Jeong et al., p. 6529.

Prognostic significance of VEGF signaling system components and matrix metalloproteinases in blood serum of gastric cancer patients.

Analysis of long-term treatment results of 77 primary gastric cancer patients at stage I-IV of the tumor process followed during 1 - 41 months (median - 6.4 months) from the onset of specific treatment are presented depending on the basal levels of VEGF, soluble forms of its receptors (sVEGFR1, sVEGFR2) and matrix metalloproteinases (MMP-2, 7, 9) in blood serum. Overall survival assessed by Kaplan-Meyer analysis and with the help of Cox multiparametric regression model was applied as the criterion of prognostic value. It was found that at high (≥ 420 pg/ml) serum VEGF, the overall survival of patients with gastric cancer was statistically significantly lower than at the marker's levels below 420 pg/ml (p<0.011): 3-year's survival comprised 46,3±12,5% and 88,2±7,8% respectively. Median survival of patients with high VEGF level comprised 21.7 months, of those with low VEGF was not achieved during the whole follow-up period. Serum sVEGFR1, sVEGFR2, MMP-2, 7 and 9 levels were not significantly associated with the overall survival of patients included in this study. Only index M of TNM system and serum VEGF level demonstrated an independent prognostic value in multiparametric model (p=0.036). Thus, it was confirmed that VEGF signaling pathway plays an important role in gastric cancer, and its components - in the first place, VEGF A - are substantial factors of disease prognosis, and can also be useful for monitoring of treatment efficiency.