Intestinal-type Gastric Cancer Research Articles

HAND2-AS1, PRKAA2 and VLDLR predict the risk of peritoneal metastasis in gastric cancer of different Lauren types based on STEPP analysis

The peritoneum is the most common site of recurrence of gastric cancer (GC). Early occult peritoneal metastasis is difficult to detect by imaging examination. Stratifying the risk of peritoneal metastasis in patients with different Lauren subtypes is of great clinical value. We performed a univariate Cox regression to identify those genes with prognostic value of overall survival (OS) and peritoneal-specified disease-free survival (psDFS) from the Gene Expression Omnibus database. The candidate genes were screened by the Subpopulation Treatment Effect Pattern Plot (STEPP) method. Propensity score matching (PSM) analysis was used to reduce the interference of confounders on the results. Based on the optimal cut-off values determined by the STEPP method, we found overexpression of three genes (HAND2-AS1, PRKAA2, and VLDLR) was correlated with shorter 1-year psDFS among patients with diffuse-type than that of patients with intestinal-type GC, and it is highly significant. Gene Set Enrichment Analysis (GSEA) potentially suggested that the three genes promote the early occurrence of peritoneal metastasis in patients with diffuse-type GC through glucose metabolism-related pathways. These three genes may be potential biomarkers. They can be used to assess the risk of peritoneal metastases to guide treatment decisions and follow-up strategies.

HAND2-AS1, PRKAA2 and VLDLR predict the risk of peritoneal metastasis in gastric cancer of different Lauren types based on STEPP analysis

The peritoneum is the most common site of recurrence of gastric cancer (GC). Early occult peritoneal metastasis is difficult to detect by imaging examination. Stratifying the risk of peritoneal metastasis in patients with different Lauren subtypes is of great clinical value. We performed a univariate Cox regression to identify those genes with prognostic value of overall survival (OS) and peritoneal-specified disease-free survival (psDFS) from the Gene Expression Omnibus database. The candidate genes were screened by the Subpopulation Treatment Effect Pattern Plot (STEPP) method. Propensity score matching (PSM) analysis was used to reduce the interference of confounders on the results. Based on the optimal cut-off values determined by the STEPP method, we found overexpression of three genes (HAND2-AS1, PRKAA2, and VLDLR) was correlated with shorter 1-year psDFS among patients with diffuse-type than that of patients with intestinal-type GC, and it is highly significant. Gene Set Enrichment Analysis (GSEA) potentially suggested that the three genes promote the early occurrence of peritoneal metastasis in patients with diffuse-type GC through glucose metabolism-related pathways. These three genes may be potential biomarkers. They can be used to assess the risk of peritoneal metastases to guide treatment decisions and follow-up strategies.

Molecular network analysis of RNA viral infection pathway in diffuse- and intestinal-type gastric cancer

Molecular network analysis of RNA viral infection pathway in diffuse- and intestinal-type gastric cancer

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis.

Previous studies have demonstrated the in vitro oncogenic role of protein arginine methyltransferase 5 (PRMT5) in gastric cancer cell lines. The in vivo function of PRMT5 in gastric tumorigenesis, however, is still unexplored. Here, we showed that Prmt5 deletion in mouse gastric epithelium resulted in spontaneous tumorigenesis in gastric antrum. All Prmt5-deficient mice displayed intestinal-type gastric cancer within 4 months of age. Of note, 20% (2/10) of Prmt5 mutants finally developed into invasive gastric cancer by 8 months of age. Gastric cancer caused by PRMT5 loss exhibited the increase in Lgr5+ stem cells, which are proposed to contribute to both the gastric tumorigenesis and progression in mouse models. Consistent with the notion that Lgr5 is the target of Wnt/β-catenin signaling, whose activation is the most predominant driver for gastric tumorigenesis, Prmt5 mutant gastric cancer showed the activation of Wnt/β-Catenin signaling. Furthermore, in human gastric cancer samples, PRMT5 deletion and downregulation were frequently observed and associated with the poor prognosis. We propose that as opposed to the tumor-promoting role of PRMT5 well-established in the progression of various cancer types, PRMT5 functions as a tumor suppressor in vivo, at least during gastric tumor formation.

Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population.

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

Increased tensin 4 expression is related to the histological type of gastric cancer.

BACKGROUNDGastric cancer (GC) is one of the most common malignant tumors worldwide. Tensin 4 (TNS4) is an adhesive protein belonging to the tensin family. This protein is located in focal adhesion sites. The TNS4 gene is considered an oncogene in numerous cancers. This protein plays an important role in adhesion, migration and proliferation of cells.AIMTo evaluate expression of TNS4 protein in GC tissues and analysis of the clinical and histopathological parameters as well as the overall survival rate of patients.METHODSThe expression of TNS4 was assessed in 89 patients using immunohistochemistry.RESULTSPositive expression of TNS4 was observed in 49 of 89 patients (55.06%). Higher TNS4 expression was more common in GC tumors with a diameter ≥ 5 cm (P = 0.040). We demonstrated that an increase in TNS4 expression was more frequent in tumors of the histological type without mucinous components than in tumors from mucosal cancers (P = 0.023). Furthermore, TNS4 expression was higher in moderately differentiated tumors than in poorly differentiated and non-differentiated tumors (P = 0.002). Increased TNS4 expression was also noted in the intestinal type of GC according to Lauren’s classification (P = 0.020). No statistically significant correlation was found between the expression of TNS4 and the overall survival rate of patients.CONCLUSIONTNS4 expression was significantly higher in tumors with a diameter ≥ 5 cm of the moderately differentiated intestinal type (according to Lauren’s classification) of GC without a mucinous component. Therefore, increased TNS4 expression is related to the histological type of GC with a better prognosis.

Advances in the Aetiology & Endoscopic Detection and Management of Early Gastric Cancer.

Simple SummaryGastric adenocarcinoma has remained a highly lethal disease. Awareness and recognition of preneoplastic conditions (including gastric atrophy and intestinal metaplasia) using high-resolution white-light endoscopy as well as chromoendoscopy is therefore essential. Helicobacter pylori, a class I carcinogen, remains the main contributor to the development of sporadic distal gastric neoplasia. Management of early gastric neoplasia with endoscopic resections should be in line with standard indications. A multidisciplinary approach to any case of an early gastric neoplasia is imperative. Hereditary forms of gastric cancer require a tailored approach and individua-lized surveillance.The mortality rates of gastric carcinoma remain high, despite the progress in research and development in disease mechanisms and treatment. Therefore, recognition of gastric precancerous lesions and early neoplasia is crucial. Two subtypes of sporadic gastric cancer have been recognized: cardia subtype and non-cardia (distal) subtype, the latter being more frequent and largely associated with infection of Helicobacter pylori, a class I carcinogen. Helicobacter pylori initiates the widely accepted Correa cascade, describing a stepwise progression through precursor lesions from chronic inflammation to gastric atrophy, gastric intestinal metaplasia and neoplasia. Our knowledge on He-licobacter pylori is still limited, and multiple questions in the context of its contribution to the pathogenesis of gastric neoplasia are yet to be answered. Awareness and recognition of gastric atrophy and intestinal metaplasia on high-definition white-light endoscopy, image-enhanced endoscopy and magnification endoscopy, in combination with histology from the biopsies taken accurately according to the protocol, are crucial to guiding the management. Standard indications for endoscopic resections (endoscopic mucosal resection and endoscopic submucosal dissection) of gastric dysplasia and intestinal type of gastric carcinoma have been recommended by multiple societies. Endoscopic evaluation and surveillance should be offered to individuals with an inherited predisposition to gastric carcinoma.

The upregulation of proteins light chain 3 and autophagy-related 5 and the occurence of intestinal-type gastric cancer.

This study aims to investigate the expression levels and values of autophagy genes light chain 3 (LC3) and autophagy-related 5 (ATG5) in intestinal-type gastric cancer. Ninety samples of normal gastric mucosa, intraepithelial neoplasia, and gastric cancer tissue were used in this study. The messenger ribonucleic acid (mRNA) and protein expression levels of autophagy genes LC3 and ATG5 were detected using quantitative reverse transcription polymerase chain reaction, Western blot, and the immunohistochemistry method. The correlations of the autophagy genes and certain clinical pathological parameters were analyzed. The results showed that LC3 mRNA expression was 43.76 ± 20.31 in the normal group, 111.29 ± 18.65 in the intraepithelial neoplasia group, and 131.78 ± 26.29 in the gastric cancer group, while ATG5 mRNA expression was 4.52 ± 2.37 in the normal group, 7.09 ± 1.88 in the intraepithelial neoplasia group, and 10.25 ± 2.81 in the gastric cancer group. The differences between the groups were statistically significant (P < 0.05). The protein expression of LC3 in the normal group was 1.05 ± 0.41, 1.53 ± 0.36 in the intraepithelial neoplasia group, and 1.99 ± 0.14 in the gastric cancer group. The protein expression of ATG5 was 0.78 ± 0.24 in the normal group, 1.37 ± 0.39 in the intraepithelial neoplasia group, and 2.04 ± 0.63 in the gastric cancer group. The differences between the groups were statistically significant (P < 0.05). The positive rate of LC3 protein expression was 33.3% in the normal group and 60% in the intraepithelial neoplasia group, and the difference was statistically significant (χ2 = 4.89; P = 0.04). In the gastric cancer group, the positive rate of LC3 protein expression was 83.3%, making it significantly higher than the intraepithelial neoplasia group, with a statistically significant difference (χ2 = 4.02, P = 0.045). The positive rate of ATG5 protein expression was 23.3% in the normal group, 50.0% in the intraepithelial neoplasia group, and 76.7% in the gastric cancer group. The expression in the intraepithelial neoplasia group was much higher than in the normal group, with a statistically significant difference (χ2 = 4.59, P = 0.03), and that of the gastric cancer group was much higher than that of the intraepithelial neoplasia group, with a statistically significant difference (χ2 = 4.59, P = 0.03). LC3 protein expression was significantly correlated with depth of infiltration, and lymph node status. ATG5 protein expression was significantly correlated with age, depth of infiltration, and lymph node status. There was also a correlation between the LC3 and ATG5 proteins (correlation coefficient r = 0.72, P = 0.001). The enhanced autophagy activity of LC3 and ATG5 may participate in the occurrence and development of intestinal gastric cancer, and they may play a synergistic role in promoting the occurrence and development of intestinal gastric cancer. These findings provide clinical value for the diagnosis of intestinal gastric cancer.

Is intestinal metaplasia the point of no return in the progression of gastric carcinogenesis?

Is intestinal metaplasia the point of no return in the progression of gastric carcinogenesis?

Prognostic factors to predict the survival in patients with advanced gastric cancer who receive later-line nivolumab monotherapy-The Asahikawa Gastric Cancer Cohort Study (AGCC).

BackgroundChemotherapy for advanced gastric cancer is recommended in the guidelines; however, later‐line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens.Patients and methodsA regional cohort study was undertaken to determine the real‐world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated.ResultsIn total, 70 patients who received nivolumab as ≥third‐line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8–10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68–0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2‐positive status (27.3%) or microsatellite instability‐high (27.3%) status.ConclusionsThe regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer.

Simple SummaryThe epithelial-mesenchymal transition (EMT) is an important hallmark in drug resistance and cancer malignancy in cancer stem cells (CSCs). In this study, gene expression in diffuse- and intestinal-type gastric cancer (GC) was investigated to reveal the precise mechanism of EMT. The pathways of cell cycle regulation and DNA damage response were found to be altered in diffuse- and intestinal-type GC. The findings of this study may provide broader insights into CSCs, with new possibilities of the involvement of the cell cycle in EMT.Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.

18F-fluorodeoxyglucose uptake in advanced gastric cancer correlates with histopathological subtypes and volume of tumor stroma

PurposeThe aim of this study was to investigate the correlation between preoperative 18F-fluorodeoxyglucose (FDG) uptake and histological subtypes, amount of tumor stroma in advanced gastric cancer (GC), and clinical outcomes. MethodsWe evaluated 56 patients (male/female, 42:14; mean age, 69 years) with advanced GC who underwent surgical resection at our institution and positron emission tomography–computed tomography with 18F-FDG prior to surgery. We used the maximum standardized uptake value (SUVmax) of the tumor and the tumor-to-liver ratio (TLR) of the SUVmax for the analysis. The SUVmax and TLR correlated with histological subtypes, immunohistochemistry (IHC) for CD34, and recurrence-free survival (RFS). Tumor stroma in GC was evaluated by CD34 expression. GCs were classified according to the Lauren and World Health Organization (WHO) classifications. ResultsThe average FDG uptakes (SUVmax) were 4.17% and 14.04% in diffuse and intestinal type GCs, respectively, according to the Lauren classification, and 4.17%, 13.87%, 7.70%, 9.71%, and 19.45% in the poorly cohesive, tubular, mucinous, and papillary adenocarcinomas, respectively, according to the WHO classification. The FDG uptake in diffuse type was significantly lower than that in the intestinal type (p = 0.000). The SUVmax and TLR of the CD34(+) group (mean SUVmax, 5.50; TLR, 1.56) were significantly lower than those of the CD34(−) group (mean SUVmax, 14.09; TLR, 4.09). RFS was not associated with TLR or CD34 expression. ConclusionGC, which has abundant tumor stroma characterized by high CD34 expression on IHC, shows low FDG uptake.

Poor oral hygiene behavior is associated with an increased risk of gastric cancer: A population-based case-control study in China.

Poor oral health may be a significant risk factor for gastric cancer (GC); however, previous results are not consistent. Here, we investigated the effect of oral health on GC and effect modification by other factors. We conducted a population-based case-control study in Taixing, China. Participants aged between 40 and 85 years and who had lived in Taixing for at least 5 years were included. The GC cases were confirmed by endoscopy and pathological diagnosis, and the controls were randomly selected using the frequency-matching method. Unconditional logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (CIs) of oral health for GC risk after adjusting for confounders and risk factors. Overall, 901 GC cases and 1972 controls were included. Tooth loss was not significantly associated with an increased risk of GC (yes vs. no, OR=1.08, 95% CI 0.88 to 1.33). Compared with toothbrushing at least twice per day, toothbrushing once per day or less was associated with an increased risk of GC (OR=2.39, 95% CI 1.94 to 2.94), and was more pronounced in esophagogastric junction cancer and intestinal-type GC. There was no significant interaction between the indicators of oral health and age, sex, tobacco smoking, alcohol drinking, and Helicobacter pylori seropositivity. Poor oral hygiene behavior is associated with an increased risk of GC, and this positive association is consistent across all GC subgroups classified by anatomy and histology. Further studies are needed to explore the possible mechanisms behind this association.

Prognostic Value of LncRNA KRT18P55 in Patients with Intestinal Type of Gastric Cancer.

Gastric cancer (GC) is a heterogeneous disease, and this heterogeneity significantly affects survival and treatment outcomes. Identification of molecular biomarkers specific for early-stage GC can help clinicians to choose more precise and effective treatment approaches. Long non-coding RNAs (lncRNAs) have the potential to be used as biomarkers because of their tissue specificity, stability, and availability in body fluids. In this study, we aimed to investigate changes in the expression levels of lncRNA KRT18P55 and to assess its biomarker potentials in patients with GC. Tumor and non-tumor marginal tissues were collected from 102 patients at Noor-Nejat Hospital (Tabriz, Iran). RNA was isolated, and quantitative reverse transcriptase PCR (qRT-PCR) was performed to assess KRT18P55 expression levels in tumor and non-tumor tissue samples. The receiver operating characteristic (ROC) curve analysis was performed to evaluate potentials of KRT18P55 as a prognostic biomarker in GC. SPSS and GraphPad Prism software were used for data analysis. We found that KRT18P55 is significantly overexpressed in tumor as compared to non-tumor tissues (p < 0.0001). We found a significant association between KRT18P55 overexpression and intestinal GC subtype (p < 0.0001), lymph node metastasis (p = 0.013), and Helicobacter pylori infection (p = 0.033). Based on the ROC analysis, KRT18P55 showed a sensitivity and specificity of 53.92% and 77.45%, respectively. Overexpression of KRT18P55 in gastric tumors is suggestive of its oncogenic role in GC. In addition, KRT18P55 may be used as a potential prognosis biomarker and therapeutic target in intestinal GC subtype.

Prognostic Significance of p27 and Survivin in H. pylori Gastritis and Gastric Cancer.

Objective:to assess expression of p27 and survivin in chronic gastritis with/without H. pylori ± intestinal metaplasia (IM) and in intestinal-type gastric cancer (IGC). Materials and Methods:Immunohistochemical staining for p27 and survivin on paraffin-embedded sections of 20 chronic gastritis, 20 H. pylori gastritis, 15 H. pylori gastritis with IM, 50 IGC, and 10 controls. Positivity (number of positive cases) and expression (mean percentage of positive gastric cells) for both proteins were evaluated. Results:P27 positivity and expression decreased from control to chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM. In IGC, p27 positivity and expression were lower than controls and chronic gastritis but higher than H. pylori gastritis ±IM. High grade and advanced stage IGCs have insignificantly lower p27 positivity and expression than low grade and early stage IGCs. By contrast, survivin positivity and expression increased from chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM to IGCs. High grade and advanced stage IGCs have significantly higher survivin positivity and expression than low grade and early stage IGCs. Males have higher positivity and expression for p27 and survivin than females. Conclusion:Inverse relation between p27 and survivin in H. pylori gastritis, H. pylori gastritis with IM and IGCs lesions, suggesting that both proteins could be used as potential prognostic and/or diagnostic biomarkers in H. pylori and IM associated- gastritis as well as in IGC.

Serum Assay Findings after Successful Helicobacter pylori Eradication

Serum pepsinogen (PG), anti-Helicobacter pylori (H. pylori) immunoglobulin G (IgG), and gastrin-17 (G-17) are plasma biomarkers for gastritis. H. pylori serology titers and PG levels increase during active H. pylori infection; moreover, elevated PG II levels indicate a high risk for diffuse-type gastric cancer in East Asian populations. Serum PG I/II ratios and PG I levels decrease with the progression of gastric corpus atrophy; thus, a combination of serum PG I levels ≤70 ng/mL and a PG I/II ratio ≤3 (serologic atrophy) indicates a high risk of intestinal-type gastric cancer. Serum G-17 is often not used as an indicator in H. pylori-seroprevalent populations because it is usually elevated in subjects with H. pylori infections. When H. pylori is eradicated, most patients show a rapid decrease in serum PG II levels and anti-H. pylori IgG titers within a few months. Seroreversion is required for several months to years after regression of H. pylori. Moreover, seroreversion may not always be achieved in all eradicated cases. The serum PG I/II ratio starts to increase after eradication; therefore, serologic atrophy improves accordingly, unless severe atrophy is present. Thus, some eradicated patients may show normal serum assay findings but have a higher risk for developing gastric cancer than H. pylori-naive subjects. Furthermore, serum PG levels decrease after gastrectomy and increase with the intake of certain drugs (e.g., aspirin or acid suppressants) or in renal failure patients. Due to such wide variations, serum assays are inadequate for the confirmation of H. pylori eradication. It is useful when interpreted with gastroscopy and other H. pylori test findings.

Value of GastroPanel in the diagnosis of atrophic gastritis.

Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), considered as precursor of the intestinal type of gastric cancer, is of growing interest. The combination of pepsinogen (PG), gastrin-17 (G17) and anti-Helicobacter pylori (H. pylori) antibody serological assays (panel test) is a non-invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of this test remains uncertain. The aim of our study was to assess the diagnostic performance of the serum panel test (GastroPanel) for the diagnosis of atrophic gastritis. From dyspeptic patients, endoscopic biopsy samples (two from the gastric corpus and two from the antrum) and blood samples were collected. The determination of sPGI, sPGII, sG17 and IgG antibodies to H. pylori (H.p IgG) was performed using an enzyme-linked immunosorbent assay (GastroPanel; Biohit Oyj). Histopathology results were compared with GastroPanel values. Sixty patients were included: 35 (58.3%) females and 25 (41.66%) males; mean age 67.63±9.36 years; 45% H. pylori-positive. A total of 65% of patients had atrophic gastritis. There were no significant differences between the levels of biomarkers and localization of atrophy. The ratio PG1/PG2 was lower in patients with multifocal atrophy; the difference being close to the threshold of statistical significance. In cases of intestinal metaplasia the values of G17, PG1, PG2, H.p IgG were not statistically altered compared to those without intestinal metaplasia; only the ratio PG1/PG2 was lower in intestinal metaplasia; the difference being almost of statistical significance. Our results revealed that, GastroPanel values did not differ depending on the severity of the atrophy. Biomarkers used by GastroPanel do not have enough accuracy for use in the diagnosis of atrophy in the population studied. A low accuracy only for the ratio PG1/PG2 in patients with multifocal atrophy was found. However, our data revealed a correlation in detecting intestinal metaplasia.

Up-regulation of Aquaporin 5 Defines Spasmolytic Polypeptide-Expressing Metaplasia and Progression to Incomplete Intestinal Metaplasia.

Background & AimsMetaplasia in the stomach is highly associated with development of intestinal-type gastric cancer. Two types of metaplasias, spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM), are considered precancerous lesions. However, it remains unclear how SPEM and IM are related. Here we investigated a new lineage-specific marker for SPEM cells, aquaporin 5 (AQP5), to assist in the identification of these 2 metaplasias.MethodsDrug- or Helicobacter felis (H felis) infection-induced mouse models were used to identify the expression pattern of AQP5 in acute or chronic SPEM. Gene-manipulated mice treated with or without drug were used to investigate how AQP5 expression is regulated in metaplastic lesions. Metaplastic samples from transgenic mice and human gastric cancer patients were evaluated for AQP5 expression. Immunostaining with lineage-specific markers was used to differentiate metaplastic gland characteristics.ResultsOur results revealed that AQP5 is a novel lineage-specific marker for SPEM cells that are localized at the base of metaplastic glands initially and expand to dominate glands after chronic H felis infection. In addition, AQP5 expression was up-regulated early in chief cell reprogramming and was promoted by interleukin 13. In humans, metaplastic corpus showed highly branched structures with AQP5-positive SPEM. Human SPEM cells strongly expressing AQP5 were present at the bases of incomplete IM glands marked by TROP2 but were absent from complete IM glands.ConclusionsAQP5-expressing SPEM cells are present in pyloric metaplasia and TROP2-positive incomplete IM and may be an important component of metaplasia that can predict a higher risk for gastric cancer development.

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma: Relation to the immune cycle.

BACKGROUNDVarious histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete.AIMTo clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODSIn total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated.RESULTSWe found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSIONThese data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Construction and Validation of a Novel Prognostic Signature for Intestinal Type of Gastric Cancer

Background Intestinal type of gastric cancer (IGC) is the largest subtype of gastric cancer (GC) by Lauren classification. The purpose of this present study was to construct a prognostic signature for IGC patients, based on the high-grade dysplasia (HGD) and IGC tissues, to improve and enhance the prognostic accuracy. Methods The microarray datasets and associated clinical characteristics of HGD and IGC were obtained from the Gene Expression Omnibus (GEO) database. Based on the differential expression analysis between HGD and IGC, the prognostic-related differential expression genes (DEGs) were identified in a training set by univariate COX regression analysis. The least absolute shrinkage and selection operator (LASSO) regression was used to construct an optimal prognostic signature. The enrichment analysis was performed by using Gene Set Enrichment Analysis (GSEA). The performance of the nomogram was assessed by the calibration curve and concordance index (C-index). The results were validated by using a testing set. Results We identified 35 prognostic-related DGEs in the training set. The nine-gene signature was established by LASSO analysis. The nine-gene signature was an independent risk factor in both the training and testing sets. The areas under the curve (AUC) values of receiver operating characteristic (ROC) analysis were 0.733 and 0.700 for the training and testing sets, respectively. In GSEA analysis, the gene expression in high-risk group was enriched in hedgehog signaling, epithelial mesenchymal transition, and angiogenesis. The nomogram for IGC showed good performance with C-index of 0.81 (95% CI: 0.76-0.86) and 0.70 (95% CI: 0.63-0.77) in the training and testing sets, respectively. Conclusion We identified and verified a nine-gene signature for the prognostic prediction of IGC patients, which might identify subgroups of IGC patients and select more suitable therapeutic options.