Expression In Gastric Adenocarcinoma Research Articles

Prognostic Significance of Hmga1, c-CBL and TNFRSF11B Expression in Gastric Adenocarcinoma

Prognostic Significance of Hmga1, c-CBL and TNFRSF11B Expression in Gastric Adenocarcinoma

Microsatellite Instability and P53 Aberrant Expression in Gastric Adenocarcinoma: Immunohistochemical Assessment and Correlation with Clinico-pathological Characteristics

Background: Gastric cancer (GC) is among the five most frequent cancer worldwide, following lung, breast, colorectal, and prostate cancer. It is the 12th most prevalent cancer in both sexes in Egypt, accounting for 1.6% of all malignancies. Distinct molecular subtypes of gastric adenocarcinoma (e.g., microsatellite instable subtype and P53 aberrant subtype) have been reported by different classification systems. However, the relation of these molecular subtypes to different clinicopathological features is still controversial.
 Aim of the Work: To utilize the immunohistochemical expression of DNA MMR proteins (MLH1 and MSH2) and p53 to detect microsatellite unstable and P53 aberrant molecular types in gastric adenocarcinoma. Moreover, to correlate immunohistochemically detected microsatellite unstable and P53 aberrant molecular types of gastric carcinoma with different clinicopathological characteristics.
 Materials and Methods: The immunohistochemical expression of MLH1, MSH2 and P53 proteins was evaluated in 70 cases of gastric adenocarcinoma.
 Results: Microsatellite status/Mismatch repair status showed a statistically significant relation with WHO classification, tumor differentiation, lymph node status, and TNM staging. P53 aberrant type showed a statistically significant relation with tumor differentiation, depth of tumor invasion, lymph node status, and TNM staging.
 Conclusions and Recommendations: Microsatellite instable GC and P53 aberrant GC are two distinct molecular subtypes of gastric adenocarcinoma with distinct clinicopathological features and different prognostic outcomes. Microsatellite instable tumors are associated with good prognostic parameters while, P53 aberrant tumors are associated with poor prognostic parameters. Both subtypes could be detected using immunohistochemistry and could represent potential targets for future therapeutic agents.

Evaluation of the TXNIP gene expression in gastric adenocarcinoma and its relationship with overall survival of patients

Background. Gastric Cancer (GC) is a common gastrointestinal tumor, and its incidence is increasing. The pathogenesis of GC is very complex and remains unclear. Recent basic studies of GC have focused on gene expression dysregulation. Accumulating evidence has demonstrated that thioredoxin-interacting protein (TXNIP) is abnormally expressed in a variety of malignant tumors but it is obscure in GC. This study aimed to compare the expression of the TXNIP gene in cancerous and adjacent tissue of gastric cancer and evaluate its clinical significance in the prognosis and survival analysis of gastric cancer patients. Methods. A total of 50 tumor tissues and marginal non-tumor control tissues were obtained from GC patients. Also, TXNIP gene expression levels were evaluated by real-time PCR. Meanwhile, bioinformatic approaches were used to evaluate TXNIP expression in two different cohorts of GC patients. A data mining study was also performed to determine the prognostic role of TXNIP expression in the overall survival of GC. Furthermore, a pan-cancer analysis of TXNIP expression was performed using TCGA data. Results. The TXNIP gene was down-regulated in tumor samples with a fold change of 0.33, and the same results were repeated in bioinformatics analysis. Decreased expression of TXNIP was significantly associated with metastasis, poor differentiation, and drug abuse. Our results provided evidence that TXNIP gene expression level is positively correlated with the overall survival of GC patients. Pan-cancer analysis of TCGA data revealed down-regulated TXNIP in a variety of malignant tumors. Conclusion. This study established low TXNIP expression as a prognostic biomarker in GC. It also revealed that the decrease in TXNIP expression likely favors metastatic GC. Practical Implications. Evaluation of TXNIP expression is informative in the prognosis of GC patients.

Quantitative parameters in novel spectral computed tomography: Assessment of Ki-67 expression in patients with gastric adenocarcinoma.

The level of Ki-67 expression has served as a prognostic factor in gastric cancer. The quantitative parameters based on the novel dual-layer spectral detector computed tomography (DLSDCT) in discriminating the Ki-67 expression status are unclear. To investigate the diagnostic ability of DLSDCT-derived parameters for Ki-67 expression status in gastric carcinoma (GC). Dual-phase enhanced abdominal DLSDCT was performed preoperatively in 108 patients with gastric adenocarcinoma. Primary tumor monoenergetic CT attenuation value at 40-100 kilo electron volt (kev), the slope of the spectral curve (λHU), iodine concentration (IC), normalized IC (nIC), effective atomic number (Zeff) and normalized Zeff (nZeff) in the arterial phase (AP) and venous phase (VP) were retrospectively compared between patients with low and high Ki-67 expression in gastric adenocarcinoma. Spearman's correlation coefficient was used to analyze the association between the above parameters and Ki-67 expression status. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic efficacy of the statistically significant parameters between two groups. Thirty-seven and 71 patients were classified as having low and high Ki-67 expression, respectively. CT40 kev-VP, CT70 kev-VP, CT100 kev-VP, and Zeff-related parameters were significantly higher, but IC-related parameters were lower in the group with low Ki-67 expression status than the group with high Ki-67 expression status, and other analyzed parameters showed no statistical difference between the two groups. Spearman's correlation analysis showed that CT40 kev-VP, CT70 kev-VP, CT100 kev-VP, Zeff, and nZeff exhibited a negative correlation with Ki-67 status, whereas IC and nIC had positive correlation with Ki-67 status. The ROC analysis demonstrated that the multi-variable model of spectral parameters performed well in identifying the Ki-67 status [area under the curve (AUC) = 0.967; sensitivity 95.77%; specificity 91.89%)]. Nevertheless, the differentiating capabilities of single-variable model were moderate (AUC value 0.630 - 0.835). In addition, the nZeff VP and nICVP (AUC 0.835 and 0.805) showed better performance than CT40 kev-VP, CT70 kev-VP and CT100 kev-VP (AUC 0.630, 0.631 and 0.662) in discriminating the Ki-67 status. Quantitative spectral parameters are feasible to distinguish low and high Ki-67 expression in gastric adenocarcinoma. Zeff and IC may be useful parameters for evaluating the Ki-67 expression.

Comprehensive analysis of COMMD10 as a novel prognostic biomarker for gastric cancer.

COMMD10 has an important role in the development of certain tumors, but its relevance to gastric cancer (GC) is unclear. The purpose of this study is to investigate the difference of COMMD10 expression in gastric adenocarcinoma (STAD) and analyze the correlation between COMMD10 expression and prognosis of STAD patients. The expression levels of COMMD10 between STAD and normal tissues were explored using the The Cancer Genome Atlas (TCGA) database. In addition, the expression of COMMD10 in GC was further validated by immunohistochemistry (IHC) staining, qRT-PCR and Western blot. Dot blot experiments were used for exploring m6A expression levels in tissues with high and low COMMD10 expression. Kaplan-Meier analysis and COX regression analysis were used to explore the relationship between COMMD10 and STAD prognosis. A nomogram was constructed to predict the survival probability of STAD patients. GO and KEGG functional enrichment of COMMD10-related genes were performed. The Corrlot software package was used to analyze the correlation between COMMD10 expression levels and m6A modifications in STAD. An analysis of immune infiltration based on the CIBERSOFT and the single-sample GSEA (ssGSEA) method was performed. COMMD10 expression was significantly associated with multiple cancers, including STAD in TCGA. COMMD10 expression was elevated in STAD cancer tissues compared to paracancerous tissues. COMMD10 upregulation was associated with poorer overall survival (OS), clinical stage, N stage, and primary treatment outcome in STAD. Functional enrichment of COMMD10-related genes was mainly involved in biological processes such as RNA localization, RNA splicing, RNA transport, mRNA surveillance pathways, and spliceosomes. The dot blot experiment showed that m6A levels were higher in cancer tissues with high COMMD10 expression compared with paracancerous tissues. COMMD10 was significantly correlated with most m6A-related genes. COMMD10 was involved in STAD immune cells infiltration, correlated with macrophage cells expression. High COMMD10 expression was significantly associated with poor prognosis in STAD patients, and its functional realization was related to m6A modification. COMMD10 involved in STAD immune infiltration.

Alteration in key oncoprotein expression in gastric adenocarcinoma - An immunohistochemical study.

This study was conducted to evaluate the frequency and clinicopathologic correlates of human epidermal growth factor receptor 2 (HER-2)/neu and betacatenin (BC) oncoproteins in gastric adenocarcinoma and to seek correlation if any between their expression status. This cross-sectional analytical immunohistochemistry (IHC) study was performed on 50 cases of gastric adenocarcinoma. HER-2/neu immunoexpression was scored as per criteria by Ruschoff et al. as positive (3+), equivocal (2+), and negative (1+, 0). Aberrant BC expression was categorized as nuclear, cytoplasmic, and reduced membranous immunoexpression. Protein expression results of both oncoproteins were correlated with conventional clinicopathological parameters. Correlation between immunoexpression profiles of both proteins was also analyzed. P <0.05 was considered statistically significant. HER-2/neu positivity (2 + and 3+) was seen in 94% of the cases; almost 60% had strong (3+) expression. All cases showed aberrant BC immunoexpression (any pattern) except 2 cases that revealed negative expression (a form of aberrant immunoexpression) and were removed from analysis due to a very small number. The pattern of BC expression was as follows: nuclear expression (38%), cytoplasmic expression (82%), reduced membranous expression (96%), no staining (4%) cases. HER-2/neu expression correlated with age. No significant correlation was found between any of the 2 oncoprotein immunoexpression and other clinicopathological parameters (P > 0.05). Concordance between protein expression of HER-2/neu and BC was seen in >93% cases, however, the correlation was not significant. HER-2/neu and BC oncoprotein expression are frequently dysregulated in gastric adenocarcinomas. The significance of pathways involving HER-2/neu and BC in gastric carcinogenesis should be explored.

Evaluation of Lymphovascular Invasion by CD31 Expression in Gastric Adenocarcinoma.

Lymphovascular tumoral invasion is a typical histopathological feature of gastric carcinomas and supports the recognition of high-risk patients for the recurrence. We aimed to study CD31 expression in diverse subtypes of gastric carcinomas and to show its association with the histopathologic findings of the carcinoma to assess the prognosis. This cross-sectional study was conducted on 40 established patients with gastric adenocarcinoma from radical gastrectomy. The patients were classified according to the pathology assessments. Tumoral tissues were assessed by immunohistochemical staining for CD31 expression. Malignant behavior was estimated by histopathological evaluations. CD31 positivity was described in 23 (57.5%) of all evaluated patients. In assessment of CD31 expression and tumor features presented, no significant association between the CD31 expression and patients' age, sex, tumor site, size, grade and stage, subtypes of carcinoma, perineural invasion, and also lymphovascular invasion was found. (P>0.05). Lymphovascular invasion may make valuable additional evidence and may be useful to detect gastric carcinoma patients at high risk for recurrence, who could be candidates for more supplementary therapies. However, in our study, CD31 expression did not show any association with the aggressive histopathologic features of this tumor.

A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma.

This study aimed to examine B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) in gastric adenocarcinoma (GAC) and its association with the maximal standard uptake value (SUVmax) of preoperative fluorine-18-fludeoosyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinicopathological data were retrospectively collected from 60 primary GAC patients. The Bmi-1 protein expression in GAC and adjacent noncancerous tissues was examined by immunohistochemistry and western blot analysis. Pearson's correlation analysis was conducted to assess the correlation between Bmi-1 expression and the SUVmax. The Bmi-1 protein levels were significantly greater in GAC versus noncancerous tissues, and higher Bmi-1 was significantly correlated with a lower degree of tumor differentiation, higher tumor stages, more lymph node metastasis, and depth of invasion. The SUVmax value was significantly correlated with the T stage, N stage, and clinical stage, but not with age, gender, tumor size, histological differentiation degree, or Lauren classification. Moreover, a significant positive correlation between Bmi-1 and SUVmax was observed in GAC tissues. In conclusion, our findings demonstrate a novel correlation between Bmi-1 and preoperative SUVmax in GAC patients who did not receive radiotherapy, chemotherapy, or targeted treatment before surgery, and both are positively correlated with unfavorable prognostic factors and a higher grade of malignancy.

PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance.

The upregulation of programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor 2 (HER2) may play a role in gastric adenocarcinoma (GAC). To study PD-L1 and HER-2 expression and prognosis in GAC. PD-L1 and HER2 expression was determined in tumor tissues of 75 patients with GAC. The correlations between PD-L1, HER2 expression, and clinicopathological factors were analyzed. The positive expression rate for PD-L1 was 57.3% (43/75) and the HER2 over-expression rate was 17.3% (13/75). PD-L1 expression negatively correlated with the grade of GAC differentiation (r =-0.26, P<0.05). Approximately 85% of HER2-positive GACs were found to be PD-L1-positive and PD-L1 expression positively correlated with HER2 overexpression. The TNM stage and combined HER2 and PD-L1 expression were independent prognostic factors affecting the survival of patients with GAC. The median overall survival and recurrence-free survival of groups I (HER2 overexpression and PD-L1 positive), II (HER2 overexpression and PD-L1 negative), III (No HER2 overexpression and PD-L1 positive) and IV (No HER2 overexpression and PD-L1 negative) were (47 (17-77), 15 (0-44), 81 (62-101), and 78 (60-98) months, respectively. PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.

Clinicopathological and prognostic significance of DNA mismatch-repair protein expression in gastric adenocarcinoma

Although the significance of DNA mismatch repair (MMR) protein expression in colorectal cancer is well-established, it remains contentious in extra-colorectal cancers and mainly in gastric adenocarcinoma. Data from Africa and Arab world remain limited. This study explored the MMR expression in gastric adenocarcinoma and evaluated its clinicopathological and prognostic signification among Tunisian patients. A retrospective study of 72 gastric adenocarcinomas was carried out. Clinicopathological particularities and patient outcomes were recorded. MMR expression was determined by immunohistochemistry on whole sections of archived material. Survival analysis was realized utilizing the Kaplan-Meier estimates and Log-Rank test. Expression of MMR proteins was observed in 84.7% of gastric adenocarcinoma samples. The 11 remaining samples (15.3%) exhibited an altered pattern of MMR protein. A significant association was identified between deficient MMR expression and advanced age (p = 0.03), intestinal type (p = 0.04) and lymph node metastases (p = 0.04). No other significant relationship was observed with the remaining selected tumor features. Patient survival was significantly associated with lymph node invasion (p = 0.002), distant metastases (p = 0.02) and tumor differentiation (p = 0.03), but not with MMR status (p = 0.83). MMR deficiency was related to advanced-age, intestinal type and nodal metastasis, but not to survival of Tunisian patients with gastric adenocarcinoma. Larger multicenter studies with additional molecular investigation are required to more explore these tumors.

Analysis of cathepsin S expression in gastric adenocarcinoma and in Helicobacter pylori infection.

Recent experimental studies have suggested a potential link between cathepsin S (CTTS) and gastric adenocarcinoma progression. Herein, we aimed to evaluate the expression of CTTS in gastric adenocarcinoma in patients who underwent curative-intent surgical resection. This was a cross-sectional study that included two groups: gastric adenocarcinoma (n = 42) and gastritis (n = 50). The gastritis group was then subdivided into H. pylori-positive (n = 25) and H. pylori-negative (n = 25) groups. Gastric tissue samples were analysed to determine CTTS expression through immunohistochemistry. Samples were obtained by oesophagogastroduodenoscopy or surgical specimens. In patients with gastritis, the age ranged from 18 to 78 years. Among them, 34% were male, and 66% were female. In patients with gastric adenocarcinoma, the age ranged from 37 to 85 years. Among them, 50% were male. When comparing the expression of CTTS between the two groups, only 16% of the gastritis samples had an expression higher than 25%. Alternatively, among patients with gastric adenocarcinoma, 19% had expression between 25-50%, 14.3% between 51-75%, and 26.2% had expression higher than 75% (p < 0.001). In the gastritis group, CTTS expression was significantly higher in patients with a positive test for H. pylori than negative test for H. pylori: 87.5% and 38.5%, respectively (p<0.001). There was no statistically significant association between CTTS positivity and clinicopathological variables, including tumour staging, histological type, angiolymphatic invasion, recurrence, current status and death. CTTS expression is higher in gastric adenocarcinoma samples. Patients with gastritis due to H. pylori also show a higher expression of CTTS than patients with negative results for this bacterium.

Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients. One hundred and twenty-eight serum and tissue samples of GAC, 20 serum and tissue samples of gastritis patients and 77 serum, 5 tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson's Chi-square test. Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r= 0.2801, P= 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r= 0.3251, P= 0.002) while not in stromal cells (r= 0.07676, P= 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P= 0.0020) or with Infiltration depth T1/T2 (P= 0.0169) or with no lymph node metastasis (P= 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P= 0.0150) or with no lymph node metastasis (P= 0.182). Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients.

CD10 expression in gastric adenocarcinoma and its correlation with histopathological features and lymph node metastasis

Background: Gastric cancer is one of the most common cancers worldwide. Invasion and metastasis are known prognostic factors. Previous studies have suggested CD10 expression in the epithelium and stroma of various carcinomas is associated with more aggressive behavior of the tumor. Aims and Objective: To study the immunohistochemical expression of CD10 in stromal cells of gastric adenocarcinoma and to correlate the expression with various clinicopathological features and lymph node metastasis. Materials and Methods: A cross sectional study of CD10 expression in 40 cases of gastric carcinoma in gastrectomy specimens was done. CD10 expression was correlated with age, gender, tumor site, tumor grade, histologic sub type, depth of invasion and lymph node status. Results: Out of 40 cases, 72.5% were males and 27.5% were females. Majority of cases were seen in 6th and 7th decades. Antrum was the most common location (70%) and intestinal morphology was the commonest histologic subtype (47.5%). Tumor size ranged from 2.5 to 11cms. 40% tumors were well differentiated. Majority (62.5%) of the tumors were in T3 stage. 25 (62.5%) cases showed a positive CD10 expression in stromal cells. Stromal CD10 expression in gastric carcinoma did not correlate with the age and gender of the cases as well as the location and size of the tumor, histologic subtype and lymph node involvement but correlated with depth of invasion (T stage) (p &lt;0.05). Conclusion: CD10 expression in gastric adenocarcinoma shows a significant correlation with depth of invasion. CD10 may be used as an immunohistochemical surrogate of tumor behavior.

The antioncogenic effect of Beclin-1 and FOXP3 is associated with SKP2 expression in gastric adenocarcinoma: Erratum.

The antioncogenic effect of Beclin-1 and FOXP3 is associated with SKP2 expression in gastric adenocarcinoma: Erratum.

An integrated analysis of DNA promoter methylation, microRNA regulation, and gene expression in gastric adenocarcinoma.

BackgroundGastric adenocarcinoma (GAC), a common type of gastric cancer, poses a significant public health threat worldwide. This study aimed to determine the transcriptional regulatory mechanisms of GAC.MethodsHTSeq-FPKM raw data were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma data collection. Subsequently, the limma package in R was used to identify differentially expressed genes (DEGs). Differentially methylated genes (DMGs), DEGs, and differentially expressed microRNAs (miRNAs) in normal, and tumor tissues of the same patients were screened and compared using R software tools. A functional enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) for various DEGs, DMGs, promoter methylation, and miRNAs. DEG-specific methylation and transcription factors were analyzed using ENCODE ChIP-seq.ResultsDEGs were centrally modified by the histone trimethylation of lysine 27 on histone H3 (H3K27me3). Upstream transcription factors of DEGs were enriched in different ChIP-seq clusters, such as Forkhead Box M1, E2F Transcription Factor 4, and suppressor of zest 12. Integrated regulatory networks of DEGs, promoter methylation, and miRNAs were constructed. Two miRNAs (hsa-mir-1 and hsa-mir-133a) and four DEGs (A disintegrin and metalloproteinase domain 12, transcription factor AP-2 alpha, solute carrier family 5 member 7, and cadherin 19) separately played important roles in the integrated regulatory network. Therefore, these DEGs, DMGs, promoter methylation, and miRNAs may play an important role in GAC pathogenesis.ConclusionsIn summary, the present study results provide insights into the oncogenesis and progression of GAC, thus accelerating the development of novel targeted GAC therapies.

The antioncogenic effect of Beclin-1 and FOXP3 is associated with SKP2 expression in gastric adenocarcinoma.

An overexpression of S-phase kinase-associated protein 2 (SKP2) is frequently observed in human cancer progression and metastasis, and evidence suggests that SKP2 plays a proto-oncogenic role both in vitro and in vivo. However, the function of SKP2 in gastric adenocarcinoma remains largely obscure. We investigated SKP2 expression in human gastric carcinomas.Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected from 2006 to 2012. Immunohistochemical staining for SKP2, Beclin-1, and forkhead box protein P3 (FOXP3) was performed. Pearson chi-square test was used to evaluate the associations among clinicopathological variables. The Kaplan–Meier method, the log-rank test, and the Cox proportional-hazards model were used in the analysis of the overall survival (OS) and disease-free survival (DFS).As a result, SKP2 overexpression in gastric adenocarcinomas showed a significant correlation with several favorable clinical factors, including the tumor size, T category, N category, lymphatic invasion, vascular invasion, OS, and DFS. SKP2 expression was positively correlated with the tumoral FOXP3, Beclin-1 expression, and regulatory T cell (Treg) infiltration. The difference in DFS between the SKP2 positive and negative group was attenuated by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration. Attenuation of the difference in OS by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration was not significant. In multivariable analysis, SKP2 expression was not correlated with OS and DFS.Our study showed a complex interrelationship between SKP2 and Beclin-1 and FOXP3 expression in gastric adenocarcinoma. The antioncogenic effect of Beclin-1 and FOXP3 expression in gastric adenocarcinoma is related to SKP2 expression.

SPP1 Regulates Radiotherapy Sensitivity of Gastric Adenocarcinoma via the Wnt/Beta-Catenin Pathway.

Purpose Radiotherapy has been widely applied for the treatment of locally advanced and metastatic gastric adenocarcinoma (GAC). The aberrant expression of secreted phosphoprotein 1 (SPP1) is involved in radiosensitivity in a variety of cancers. The present study aims to characterize the clinical significance of SPP1 expression in GAC and its role and underlying mechanism of radiosensitivity. Methods The SPP1 expression in GAC tissues and pericarcinomatous tissues was determined by QRT-PCR and immunohistochemistry, and the SPP1 expression in GAC cell lines (BGC823, AGS, and SGC7901) and normal human gastric epithelial cell line (GES-1) was determined by western blot. T-test, one-way ANOVA, Cox regression model, and Kaplan–Meier plotter were applied to further assess the association between SPP1 expression and the prognosis of the patients with GAC. After irradiation and transfection with si-SPP1 combined with or without Wnt/β-catenin pathway inhibitor (XAV939), western blot, transwell, flow cytometry, and TOP-flash reporter assay were applied to detect DNA damage, invasion, apoptosis, cell cycle, and activation of Wnt/β-catenin pathway, respectively. Results SPP1 mRNA and protein levels in GAC tissues were both dramatically higher than those in pericarcinomatous tissues. SPP1 overexpression was positively associated with tumor size, nodal status, and histological grade of GAC patients. SPP1 overexpression, depth of invasion, and nodal status were independent prognostic factors for the patients. High SPP1 expression was negatively related to the overall survival in patients with GAC. We found that SPP1 knockdown enhanced the radiosensitivity of GAC cell lines (AGS and SGC7901). Increasing H2AX phosphorylation, apoptosis and G2/M phase arrest, and decreasing invasion were observed after the administration of si-SPP1 and irradiation. Radiosensitivity of SPP1 was mainly dependent on the Wnt/β-catenin signal pathway. XAV939 could enhance these phenomena induced by irradiation combined with SPP1 knockdown. Conclusion This study demonstrates that SPP1 suppresses Wnt/β-catenin signaling to enhance the radiosensitivity of GAC via inhibiting invasion and accelerating DNA damage, G2/M phase arrest, and apoptosis.

ADAM10 expression in gastric adenocarcinoma: Results of a curative gastrectomy cohort.

Objective:Gastric cancer is among the most common human cancers with high mortality rates. ADAM10, a member of the ADAM (a disintegrin and metalloproteinase) family has also been found to be associated with gastric carcinoma and has been suggested as a potential therapeutic target. Here, we investigated the association of ADAM10 expression with prognosis in gastric adenocarcinoma patients that underwent gastric resection with D2 lymph node dissection.Methods:Total 86 consecutive patients that underwent resection for gastric adenocarcinoma were included. Immunohistochemical ADAM10 expression and its association with clinicopathological parameters were analyzed. Univariate and multivariate analyses and survival analyses were performed using SPSS ver.22.Results:High grade tumors, advanced stage tumors and diffuse type tumors showed significantly worse prognosis. A statistically significant association between ADAM10 expression and overall survival (OS) was observed in the univariate analysis, however, this association did not maintain its significance in the multivariate analysis. No statistically significant association was found ADAM-10 expression and clinicopathological parameters.Conclusion:Immunohistochemical ADAM10 expression may be used as a prognostic marker in gastric adenocarcinoma, however, introduction of a standardized immunohistochemical scoring system seems to be necessary for evaluation of ADAM10 staining.

High Concordance of HER2 Overexpression by Immunohistochemistry on Mucosal Biopsies and Resection in Gastric Adenocarcinoma

Introduction: High expression of Human Epidermal growth factor Receptor 2 (HER2) is a predictive biomarker for the treatment of gastric carcinomas with targeted agents. Targeted therapy could improve the outcome of patients with gastric carcinoma overexpressing HER2. There is limited information on mucosal biopsies to characterise the HER2 expression status of a tumour. Aim: To study HER2 expression by Immunohistochemistry (IHC) in matched mucosal biopsies and surgical specimens in patients with gastric adenocarcinoma and to discover the level of concordance. Materials and Methods: This was a prospective observational study conducted in the Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India, for one year (1st July 2016 to 30th June 2017). The IHC for HER2 was performed on matched mucosal biopsies and corresponding gastrectomy specimens of 72 patients. The HER2 overexpression (HER2+) was defined by a score 3+ on IHC. The results were analysed using Statistical Package for the Social Sciences (SPSS) software and Chi-square test was done for statistical significance. Results: The overall HER2 positivity rate was 11.11% (8/72). The HER2 positive rates (score 3+) were 9.72% on biopsy (7/72) and 8.33% on resection (6/72). Five cases showed concordance of HER2 between mucosal biopsies and resection specimens, however the other three cases showed a discordance i.e., two mucosal biopsies showed HER2 positivity and one resection showed HER2 positivity. The concordance rate in this study was 95.83% between resection and mucosal biopsies. Among the eight HER2 positive cases, five cases showed good concordance. One case showed positive shift: HER2 score was 0 on the mucosal biopsy and HER2 score was 3+ on the resection. Two cases showed a negative shift: mucosal biopsy showed HER2 score 3+ and the resection HER2 score 0. All the three discordant cases had received Neoadjuvant Chemotherapy (NACT) and showed heterogeneous staining on the resection specimen. None of the five concordant cases had received NACT and three of the five resections showed heterogeneous staining pattern. Conclusion: To the best of the authors’ knowledge, this was the first study to compare HER2 expression in gastric adenocarcinoma in matched biopsies and the corresponding resections in India. There was concordance of HER2 expression in 69 cases and discordance in three. Differences between biopsy and resection HER2 expression could be explained by intra-tumoural heterogeneity and possibly by decreased HER2 expression after NACT. The HER2 analysis by IHC on both mucosal biopsy and resections could optimise the selection of trastuzumab-eligible patients in case of gastric adenocarcinoma.

Impact of chromosome 17 centromere copy number increase on patient survival and human epidermal growth factor receptor 2 expression in gastric adenocarcinoma.

The accurate evaluation of human epidermal growth factor receptor 2 (HER2) status is essential for the appropriate use of targeted therapies. An increased number of chromosome 17 centromere enumeration probe (CEP17) signals may underrate fluorescence in situ hybridization (FISH) outcomes, resulting in false-negative or a false-equivocal HER2 status assessment. The aim of the present study was to assess the frequency of CEP17 copy number increase (CNI), its effects on HER2 protein expression (and the subsequent effects on tumor cells), and the survival outcomes of patients with gastric cancer. Archival primary tumor samples from 244 patients that underwent gastric resection for adenocarcinoma were retrieved for both HER2 protein expression analysis (using immunochemistry) and HER2 gene amplification (using FISH). The associations between HER2 status, CEP17 CNI and multiple clinicopathological parameters (including survival outcome), were assessed. The relationship between CEP17 CNI and HER2 protein upregulation was also investigated. CEP17 CNI was detected in 17.2% of cases, and a strong association between CEP17 CNI and HER2 upregulation was revealed. The impact of CEP17 CNI on survival did not reach statistical significance. Consequently, CEP17 CNI was discovered to be strongly associated with HER2 upregulation in tumor cells, which may characterize a critical issue in HER2 testing. Therefore, the eligibility for HER2-targeted agents in CEP17 CNI-positive patients warrants further recognition.