Intestinal-type Gastric Cancer Patients Research Articles

IKZF3 amplification predicts worse prognosis especially in intestinal-type gastric cancer

PurposeIKAROS family zinc finger 3 (IKZF3) is an oncogene involved in different malignancies, particularly in the development and malignant progression of lymphocytes. However, IKZF3 amplification and clinical significance in gastric cancers (GCs) remain unexplored.MethodsWe examined IKZF3 amplification status in 404 GCs with HER2 amplification status using tissue microarray (TMA) and fluorescence in situ hybridization (FISH) assays.ResultsIKZF3 amplification was detected in 6.9% (28/404) of all GC patients, with higher rates in intestinal-type gastric cancer (IGC) (11.22%, 22/196) compared to other types (2.88%, 6/208). HER2 amplification was identified in 16.09% (65/404) of all GC patients, with higher rates in IGC (20.92%, 41/196) compared to other types (11.54%, 24/208). Co-amplification of IKZF3 and HER2 was detected in 8.16% (16/196) of IGC patients and in 2.40% (5/208) of other types. IKZF3 amplification showed significant correlation with IGC (P = 0.001) and HER2 amplification (P = 0.0001). IKZF3 amplification exhibited significantly worse disease-free survival (DFS) (P = 0.014) and overall survival (OS) (P = 0.018) in GC patients, particularly in IGC (DFS: P < 0.001; OS: P < 0.001), rather than other types. Cox regression analysis demonstrate IKZF3 amplification as an independent poor prognostic factor in all GCs (P = 0.006, P = 0.004 respectively) and in IGC patients, regardless of stages I-II or III-IV (P = 0.007, P = 0.004 respectively). On the other hand, HER2 amplification was significantly associated with worse DFS (P = 0.008) and OS (P = 0.01) in IGC patients, but not in all GCs and in multivariate analysis. Within the subset of patients with HER2 amplification, those also exhibiting IKZF3 amplification displayed potential poorer prognosis (P = 0.08, P = 0.11 respectively).ConclusionIKZF3 amplification was detected in minority of GC patients, especially in IGC, and was an independent indicator of poor prognosis. Our study, for the first time, found the prognostic value of IKZF3 was superior to HER2 for GC patients.

YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration

Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.

The Clinicopathological Features and Overall Survival of Patients With Gastric Neuroendocrine Carcinoma.

Objectives:Gastric neuroendocrine carcinoma (GNEC) is a class of rare histological subtypes in gastric cancer (GC). This retrospective case-control study aimed to explore the clinicopathological features and overall survival (OS) of patients with GNEC.Methods:A large population of GNEC and intestinal-type GC (IGC) patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The 1:1 propensity score matching (PSM) analysis was initiated to adjust the confounders between GNEC and IGC cohorts. Kaplan-Meier (KM) plots with log-rank tests were used to compare the survival differences in GNEC versus IGC. Additionally, Cox proportional hazard regression models were adopted to characterize the prognostic factors relevant to OS of the GNEC patients.Results:An entity of 4596 patients were collected, including 3943 (85.8%) IGC patients and 653 (14.2%) GNEC patients. The PSM analysis well-balanced all confounders in GNEC versus IGC (all P > .05). The KM plots showed that GNEC had significantly superior OS to IGC both before and after PSM analysis. Before PSM, the median OS was 52 (33.6-70.4) months in GNEC versus 32 (29.3-34.7) months in IGC (P = .0015). After PSM, the median OS was 26 (18.3-33.7) months in GNEC versus 21 (17.7-24.3) months in IGC (P = .0039). Stratified analysis indicated that GNEC had superior survivals to IGC in early stage patients and those who received surgery. In Cox regression analysis, age ≥ 60, tumor size > 50 mm, stage II-IV, T2, and N3 were independent risk factors for the GNEC patients (hazard ratio [HR]>1, P < .05). By contrast, year 2010 to 2015, female, and surgery were independent protective factors for these patients (HR < 1, P < .05).Conclusions:GNEC has unique clinicopathological features quite different from IGC and may have a superior survival to IGC in early stage patients. The prognostic factors identified here may assist the clinicians to more individually treat these patients.

Prognostic Significances of NEDD-9 and FOXL-1 Expression in Intestinal Type Gastric Carcinoma: an Immunohistochemical Study.

Gastric cancer (GC) is mostly diagnosed at advanced stage, so prognosis is poor. Therefore, it is necessary to understand the molecular mechanism of GC development to design new targeted treatment to improve the prognosis of gastric cancer patients. To assess the prognostic value of NEDD-9 and FOXL-1 expression in intestinal type gastric cancer patients, as well as their relationship to clinicopathologic features of the disease and patients outcome. This is a retrospective study; we included 50 sections from formalin-fixed, paraffin-embedded tissue samples which included intestinal type GC and adjacent non-neoplastic gastric mucosa in the same block that were subjected to immunohistochemistry with anti-NEDD-9 and anti-FOXL-1 antibody. Patients were retrospectively followed up for about 5years for assessment of tumor progression and survival in relation to marker expression. High NEDD-9 and low FOXL-1 expression were found in intestinal type GC more than adjacent non-neoplastic mucosa (p < 0.001). NEDD-9 high expression and FOXL-1 low expression were associated with presence of helicobacter pylori gastritis (p = 0.010, 0.049), high grade (p = 0.007, 0.004), high stage (p < 0.001), presence of distant metastases (p = 0.029, 0.021), poor DFS (p = 0.003), and OS rates (< 0.001). NEDD-9 overexpression and FOXL-1 deficiency in intestinal type GC can help in prediction of tumor prognosis and it can guide the selection of patients for future therapies in gastric carcinoma.

MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK.

Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues (p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis (p < 0.05) and good prognosis (p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro. miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC.

Low periostin expression predicts poor survival in intestinal type gastric cancer patients.

Background and aimPeriostin is a protein from the Fascilin family. It is commonly present in normal tissues and is responsible for cell adhesion. Evidence has emerged showing that changes in periostin expression play an important role in tumor initiation, development, and progression. This study aims to investigate the effect of periostin in gastric cancer (GC) patients who underwent gastrectomy. Seven hundred and forty-seven GC patients who underwent gastrectomy between December 2006 and July 2011 were included in this study.MethodsSeven hundred and forty-seven cancer tissues and 70 paired adjacent normal tissues were collected. Periostin expression was evaluated by immunohistochemistry. The Gene Expression Omnibus database was used to study the association between the mRNA level and patient’s overall survival. The tumor microenvironment was also studied.ResultsPeriostin expression in stroma was downregulated in tumor tissues but it was upregulated in the epithelial cells. After dividing the tissues according to the Lauren Classification, we found that periostin expression in stroma and epithelial cells was higher in intestinal type than in diffuse type (P<0.001 and P=0.010, respectively). Periostin was an independent predictor of lymph node (LN) metastasis in GC patients. The study of CD163(+) tumor-associated macrophages (TAMs) revealed that in diffuse type GC, periostin expression was associated with CD163(+) TAMs.ConclusionWe found that the periostin expression can predict LN metastasis in patients undergoing curative gastrectomy. Intestinal type GC patients with high periostin level had both a favorable survival and lesser LN metastasis.

Expression levels of A disintegrin and metalloproteases (ADAMs), and Th17-related cytokines and their association with Helicobacter pylori infection in patients with gastroduodenal diseases.

Expression levels of A disintegrin and metalloproteases (ADAMs) (10 and 17) and Th17-related cytokines [interleukin (IL) 17A, IL-17F, IL-33, IL-23, IL-23R] were investigated by quantitative real time polymerase chain reaction in gastric biopsies of patients with different gastroduodenal pathologies in the presence and absence of Helicobacter pylori infection. Patients with gastric cancer (GC) (n = 70, intestinal-type 38 and diffuse type 32), peptic ulcer disease [n = 50, duodenal ulcer (DU) 16 and gastric ulcer (GU) 34] and functional dyspepsia (n = 120) were included in the study. Further, the expression levels of ADAMs and Th17 cytokines were correlated with H. pylori cytotoxin-associated genes pathogenicity island (cagPAI) status. Expression levels of ADAMs (10 and 17) and Th17-related cytokines (IL-17A, IL-23, IL-23R) were significantly higher in H. pylori-positive than in H. pylori-negative gastric biopsies. Significant increase in ADAM17 and Th17 cytokines (IL-17A and IL-23) expressions was observed in patients with GU and intestinal-type GC in the presence of H. pylori infection and in strains harbouring intact cagPAI. Expression levels of IL-17A, IL-23 and ADAM17 were strongly correlated with GU and intestinal-type GC and weakly with DU and diffuse-type GC in the presence of H. pylori infection. Higher expression levels of ADAM17 and Th17 cytokines (IL-17A and IL-23), and their strong correlation with GU and intestinal-type GC patients in the presence of H. pylori and its intact cagPAI status, suggest a possible role of strain specificity in the pathogenesis of these diseases.

Usefulness of OLGA and OLGIM system not only for intestinal type but also for diffuse type of gastric cancer, and no interaction among the gastric cancer risk factors.

The operative link on gastric atrophy (OLGA) and operative link on gastric intestinal metaplasia (OLGIM) stages have been suggested for risk estimation of gastric cancer (GC). However, usefulness of OLGA/OLGIM systems in diffuse type of GC was not investigated so far. The aims of this study were to evaluate the OLGA/OLGIM systems in estimating the GC risk according to Lauren's classification and to investigate the interaction among the risk factors. The OLGA/OLGIM stages were evaluated in 1398 (765 control and 633 GC patients) who were prospectively enrolled in the Seoul National University Bundang Hospital. Synergistic interaction among the risk factors for GC was calculated using an additive model. Among 387 intestinal-type GC patients, 71 (18.3%) were high-risk OLGA stages (III, IV) and 113 (29.2%) were high-risk OLGIM stages (III, IV). Of the 246 patients with diffuse-type GC, 36 (14.6%) were high-risk OLGA stages and 39 (15.9%) were high-risk OLGIM stages. Multivariable analysis revealed family history of GC, Helicobacter pylori infection, high-risk OLGA stages, and high-risk OLGIM stages as independent risk factors for GC regardless of histologic type (odds ratios [ORs] 1.78, 1.94, 2.63, and 3.18, respectively). There was no significant risk modification among the H. pylori infection, family history of GC, and high-risk OLGA/OLGIM stages. High-risk OLGA/OLGIM stages are important prediction markers for GC regardless of H. pylori infection or family history of GC not only for the intestinal type but also for diffuse-type GC.

Gene expression and prognosis of NOX family members in gastric cancer.

IntroductionNicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are frequently deregulated in several human malignancies, including gastric cancer (GC). NOX-derived reactive oxygen species have been reported to contribute to gastric carcinogenesis and cancer progression. However, the expression and prognostic role of individual NOX in GC patients remain elusive.Methods and materialsWe investigated genetic alteration and mRNA expression of NOX family in GC patients via the cBioPortal, Human Protein Atlas, and Oncomine databases. Furthermore, we evaluated prognostic value of distinct NOX in GC patients through “The Kaplan–Meier plotter” database.ResultsOur analysis demonstrated that mRNA deregulation of NOX genes was common alteration in GC patients. Compared with normal tissues, NOX1/2/4 mRNA expression levels in GC tissues were higher, while NOX5 and DUOX1/2 expression levels were lower. Importantly, our results indicated that high mRNA expression of NOX2 was associated with better overall survival whereas NOX4 and DUOX1 were correlated with worse overall survival in all GC patients, particularly in intestinal-type GC patients. In addition, our data also shed light on the diverse roles of individual NOX members in GC patients with different clinicopathological features, including human epidermal growth factor receptor 2 status, clinical stages, pathological grades, and different choices of treatments of GC patients.ConclusionThese findings suggest that individual NOX family genes, especially NOX2/4, and DUOX1, are potential prognostic markers in GC and implicate that the use of NOX inhibitor targeting NOX4 and DUOX1 may be an effective strategy for GC therapy.

A common molecular signature of intestinal-type gastric carcinoma indicates processes related to gastric carcinogenesis.

Gastric carcinoma (GC) is one of the most aggressive cancers and the second leading cause of cancer death in the world. According to the Lauren classification, this adenocarcinoma is divided into two subtypes, intestinal and diffuse, which differ in their clinical, epidemiological and molecular features. Several studies have attempted to delineate the molecular signature of gastric cancer to develop new and non-invasive screening tests that improve diagnosis and lead to new treatment strategies. However, a consensus signature has not yet been identified for each condition. Thus, this work aimed to analyze the gene expression profile of Brazilian intestinal-type GC tissues using microarrays and compare the results to those of non-tumor tissue samples. Moreover, we compared our intestinal-type gastric carcinoma profile with those obtained from populations worldwide to assess their similarity. The results identified a molecular signature for intestinal-type GC and revealed that 38 genes differentially expressed in Brazilian intestinal-type gastric carcinoma samples can successfully distinguish gastric tumors from non-tumor tissue in the global population. These differentially expressed genes participate in biological processes important to cell homeostasis. Furthermore, Kaplan-Meier analysis suggested that 7 of these genes could individually be able to predict overall survival in intestinal-type gastric cancer patients.

Association of Polymorphisms in three pri-miRNAs that Target Pepsinogen C with the Risk and Prognosis of Gastric Cancer

We aimed to explore the associations of polymorphisms in three microRNAs (miRNAs) (let-7e rs8111742, miR-365b rs121224 and miR-4795 rs1002765) that target PGC with the risk and prognosis of gastric cancer/atrophic gastritis. Sequenom’s MassArray was used to genotype the miRNA polymorphisms in 724 gastric cancer cases, 862 atrophic gastritis cases and 862 controls in a Chinese population. We found that let-7e rs8111742 and miR-4795 rs1002765 were associated with the risk of gastric cancer in the H. pylori-positive subgroup. MiR-365b rs121224 was associated with the risk of intestinal-type gastric cancer in the alcohol consumption subgroup. Intestinal-type gastric cancer patients at Borrmann stages III-IV who carry the miR-365b rs121224 GG genotype had better prognosis compared with those who carry the CG or CC genotypes. MiR-365b rs121224 was associated with Lauren typing and TNM staging, in which the distribution of GG genotype carriers in intestinal-type gastric cancer and the TNM stage I-II subgroup was higher than that of CG or CC genotypes, which contrasted with the distribution in diffuse-type gastric cancer or TNM III-IV groups. These findings suggested that the polymorphisms in these miRNAs might be biomarkers for gastric cancer risk and prognosis, especially for populations infected with Helicobacter pylori or who consume alcohol.

Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis.

In this study, we evaluated whether the presence of genetic alterations detected by next generation sequencing may define outcome in a prognostically-selected and histology-restricted population of resected gastric cancer (RGC). Intestinal type RGC samples from 34 patients, including 21 best and 13 worst prognostic performers, were studied. Mutations in 50 cancer-associated genes were evaluated. A significant difference between good and poor prognosis was found according to clinico-pathologic factors. The most commonly mutated genes in the whole population were PIK3CA (29.4%), KRAS (26.5%), TP53 (26.5%) MET (8.8%), SMAD4 (8.8%) and STK11 (8.8%). Multiple gene mutations were found in 14/21 (67%) patients with good prognosis, and 3/13 (23%) in the poor prognosis group. A single gene alteration was found in 5/21 (24%) good and 6/13 (46%) poor prognosis patients. No mutation was found in 2/21 (9.5%) and 4/13 (31%) of these groups, respectively. In the overall series, ß-catenin expression was the highest (82.4%), followed by E-Cadherin (76.5%) and FHIT (52.9%). The good prognosis group was characterized by a high mutation rate and microsatellite instability. Our proof-of-principle study demonstrates the feasibility of a molecular profiling approach with the aim to identify potentially druggable pathways and drive the development of customized therapies for RGC.

Genomic profile analysis of diffuse-type gastric cancers.

BackgroundStomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome.ResultsWe analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1, which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2-RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis.ConclusionsWe report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.

The prognostic VALUE of Ki-67 in gastric cancer.

e15172 Background: Gastric carcinoma is the second cause of cancer mortality worldwide. In Portugal, a country with a high incidence of the disease, it is also the second leading cause of cancer mortality. The gravity of this situation and the advanced stage of disease at presentation warrants a search of a new prognostic indicator. We studied in patients (pts) with gastric cancer, both diffuse and intestinal types, several possible prognostic indicators, such as: weight, nutrition status, Ki-67, p53, Cerb2, and cadherin E. The results showed that Ki-67, an indicator of cell proliferation, may play an important role as a prognostic indicator because it is easily assessed by immunohistochemistry, is observed in both intestinal and in diffuse tumor types, and is related with tumor size, depth of invasion and the pattern of lymphatic spread. Methods: A total of 50 pts with gastric carcinoma (25 diffuse and 25 intestinal types) undergoing radical gastrectomy with extended lymphadenectomy (D2 and a few D3 types ) were prospectively studied by immunohistochemistry for the determination of Ki-67 in biopsied tissue and gastrectomy specimens. A relationship between the Ki-67 and various other prognostic factors, like histological tumor type, tumor location, number of involved lymph nodes, depth of invasion, sex and stage was established. Results: A total of 50 tumor specimens and an equal number of biopsies were evaluated for Ki-67 overexpression. Ten tumors (20%) presented a Ki-67 &lt; 50%, 13 tumors (26%) showed a Ki-67 &gt;50% &lt; 74%, and 27 tumors (54%) had a Ki-67 &gt; 75%. It was found that tumors with a low Ki-67 expression have a more proximal location, the histological type was either mixed or diffuse, tend to invade superficially the gastric wall, they don’t have metastases in distal lymph nodes, and are diagnosed in early stages of the disease. Conclusions: In this study, the Ki-67 overexpression showed prognostic value in both diffuse and intestinal type gastric cancer patients.

Adiponectin receptor expression in gastric carcinoma: implications in tumor development and progression

Adiponectin, an adipocyte-secreted endogenous insulin sensitizer, appears to play an important role in progression of several malignancies. Expression of adiponectin receptors--AdipoR1 and AdipoR2--has been documented in gastric cancer (GC) cell lines, but its role in GCs is still controversial. We investigated expression level of 2 adiponectin receptors and correlated their expression with prognosis in GC patients. We immunohistochemically evaluated AdipoR1 and AdipoR2 expression in 59 non-neoplastic gastric mucosas, 48 gastric adenomas, 250 GCs, and 58 lymph nodes involved by metastatic GC and assessed its association with clinicopathologic characteristics. Expression rates of both receptors increased stepwise in non-neoplastic gastric mucosa, gastric adenoma, intestinal-type GC, and metastatic GC (p < 0.001). AdipoR1 and AdipoR2 expression was observed in 85 (34.0 %) and 118 (47.2 %) GC cases, respectively. Expression rates were higher in intestinal-type GC than in diffuse-type GC (p < 0.001 and 0.016, respectively). AdipoR1 and AdipoR2 expression was more frequent in advanced GC than in early GC (p < 0.001, each) and was associated with lymphatic invasion (p = 0.046 and 0.001, respectively). AdipoR2 expression was associated with poor overall and disease-free survival (p = 0.001 and 0.007, respectively). AdipoR1 expression was associated with poor disease-free survival for intestinal-type GC patients (p = 0.046). In multivariate analysis, AdipoR2 was an independent prognostic factor for intestinal-type GC (p = 0.017). Adiponectin receptor expression is related to GC development and progression, especially intestinal-type GC. Thus, adiponectin receptor expression can serve as a prognostic marker in GC patients.

Association of the miR‐146aC&gt;G, miR‐149T&gt;C, miR‐196a2T&gt;C, and miR‐499A&gt;G polymorphisms with gastric cancer risk and survival in the korean population

We investigated whether four common microRNA polymorphisms (miR-146aC>G [rs2910164], miR-149T>C [rs2292832], miR-196a2T>C [rs11614913], and miR-499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single-nucleotide polymorphisms (SNPs) were identified in a case-control study (461 patients; 447 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal-type gastric cancer groups, subjects with the miR-499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse-type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31-0.97; AOR = 0.57 with 95% CI = 0.33-0.97). In the stratified analyses for gastric cancer risk, the miR-146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non-smokers, whereas the miR-149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR-196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal-type gastric cancer patients with miR-146aCG + GG genotypes had significantly higher survival rates (log-rank P = 0.030) than patients with the CC genotype, and patients with the miR-499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log-rank P = 0.013). When miR-146aCG + GG and miR-499AA genotypes were combined, the survival rate of intestinal-type gastric cancer patients was elevated (log-rank P < 0.001). No association was found between gastric or diffuse-type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR-499A>G) and prognosis (miR-146aC>G and miR-499A>G) in the Korean population depending on gastric cancer type.

P-0034 An Exacerbated Pro-Inflammatory State may Increase the Risk of H. Pylori-Associated Gastric Cancer Development

IntroductionHelicobacter pylori infects the majority of the adult population worldwide and results in gastric cancer development in about one percent of the infected patients. The multifactorial etiology of gastric cancer includes the interaction between inflammatory (pro-tumor) and anti-inflammatory (anti-tumor) cytokines. In this study we aimed to evaluate the level of some of these cytokines in Iranian gastric cancer patients. MethodsFasting blood samples were collected from 93 gastric cancer and 97 cancer-free subjects. The histologic subtype of every tumor patients was intestinal in the two subsites of cardia (N=39) and non cardia (N=54). Serum samples were analyzed for IL-6, IL-7, IL-8, IL-10 and TNF-alpha using Milliplex®MAP High sensitivity human cytokine magnetic bead panel immunoassay. Statistical analyses were performed using SPSS version 11.5 software. Comparisons between each two groups were performed using Mann-Whitney U test. Differences were considered significant when P values were equal or below 0.05. ResultsMean serum values for IL-6, IL-8 and IL-10 levels were respectively 16, 2 and 9 fold greater in intestinal type gastric cancer patients versus controls (P<0.001). This phenomenon held true for both cardia (P<0.001) and noncardia (P<0.001) type gastric cancer patients. Comparison of the serum levels for IL-7 and TNF-alpha however showed no statistical difference among various clinical groups (data not shown). ConclusionIncreasing evidence is supporting the etiologic role of immune regulatory state in gastric cancer development. Our data support the fact that a shifted balance toward pro-inflammatory (IL-6, IL-8) versus anti-inflammatory (IL-10) state may increase the chances of intestinal type gastric cancer development in both cardia and noncardia subsites.

Abstract 450: Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer

Abstract Purpose. Smad interacting protein 1 (SIP1) encodes a transcription factor and is one of the epithelial-mesenchymal transition (EMT)-inducible genes that play a key role in tumor progression in various cancers. The aim of this study is to clarify the clinical significance of SIP1 expression in gastric cancer patients, and to clarify its biological function especially in intestinal type gastric cancer. Methods. We studied one hundred thirty-four patients undergoing surgery for gastric cancer. We analyzed SIP1 mRNA levels by real-time reverse transcription PCR in gastric cancer tissue and adjacent normal mucosa, and in gastric cancer cell lines. SIP1 protein expression in primary cancer and in peritoneal dissemination samples was measured using immunohistochemical analysis. Knockdown of the SIP1 gene by siRNA transfection was performed to evaluate SIP1 function in gastric cancer cell. Results. Expression of the SIP1 gene was significantly higher in cancerous tissue than in adjacent normal mucosa (p&amp;lt;0.05). Increased SIP1 expression was significantly associated with peritoneal dissemination (p&amp;lt;0.05), and was an independent prognostic factor (risk ratio, 2.17; 95% confidence interval, 1.26-3.74; p&amp;lt;0.05). Logistic regression analysis revealed that increased SIP1 expression was an independent risk factor for peritoneal dissemination (odds ratio, 3.43; 95% confidence interval, 1.25-9.43; p&amp;lt;0.05). Especially in intestinal type gastric cancer, elevated SIP1 expression was significantly correlated with peritoneal dissemination and poor prognosis (p&amp;lt;0.05). Immunohistochemical analysis indicated that SIP1 was intensely expressed in both primary cancer and peritoneal dissemination samples. In vitro, cell proliferation, migration and invasion were inhibited by SIP1 knockdown, while resistance to anoikis was decreased after knockdown of SIP1 in the intestinal type gastric cancer cell line MKN7. Conclusion: High SIP1 expression is associated with poor prognosis especially in intestinal type gastric cancer patients and enhanced malignant potential in terms of proliferation, migration, invasion and anoikis inhibition in intestinal type gastric cacner cell. These results indicate that SIP1 plays an important role in progression to peritoneal carcinomatosis in intestinal type gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 450. doi:1538-7445.AM2012-450

Abstract 4537: Tumoral expression on peroxisome proliferator-activated receptor ≤ is an independent prognostic marker in intestinal type of gastric cancer

Abstract Introduction: Peroxisome proliferator-activated receptor ≤ (PPARδ) is a member of the nuclear hormone receptor family that regulates the expression of mediators of the inflammatory response. Metaplastic change secondary to chronic inflammation of gastric mucosa is regarded as a premalignant condition of intestinal-type gastric cancer (IGC). We aimed to evaluate the prognostic significance of PPARδ in IGC patients. Methods: The clinical significance of PPARδ was explored using tissue microarray methods and immunohistochemical staining of specimens from 306 IGC patients. The Kaplan-Meier method was used to calculate survival curves, and differences between the survival curves were assessed using the log-rank test. Cox proportional hazards regression was used to assess the effect of PPARδ expression on survival while controlling for other confounding covariates. Results: Among 306 patients with IGC (stage I-IV), PPARδ expression was detected by immunohistochemistry in the tumors of 209 (68.3%). The patients with PPARδ-positive tumors had significantly lower overall and gastric cancer-specific mortalities (P = 0.0010 and 0.0016, respectively, by the log-rank test) than did those with PPARδ-negative tumors. A positive PPARδ expression was a significant independent prognostic factor for gastric cancer-specific mortality by the Cox regression analysis in patients with IGC (adjusted hazard ratio, 0.42; 95% confidence interval, 0.22-0.81). The relationship between PPARδ and lower mortality was not modified by other clinical variables including tumor stage (all Pinteraction &amp;gt; 0.05). Conclusions: tumor expression of PPARδ was independently associated with lower mortality of patients with IGC. Keywords: Gastric cancer, Intestinal-type gastric cancer, Peroxisome proliferator-activated receptor ≤ (PPARδ), Prognostic marker, Survival Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4537. doi:1538-7445.AM2012-4537

Intrafamilial aggregation of gastric cancer

Familial clustering has been reported in gastric cancer (GC). However, the mechanism of the intrafamilial aggregation of GC remains unclear. This study enrolled 123 GC relatives and their age-matched and sex-matched controls without a family history of GC, and 639 patients with GC (intestinal or diffuse type). Residence during childhood, socioeconomic status, and smoking habits were investigated as environmental factors, Helicobacter pylori (H. pylori) virulence factors (cagA, vagA s1 and m1 regions, and oipA) were evaluated, and seven biallelic polymorphisms (IL-1B-511, TNF-A-308, IL-6-572, IL-8-251, IL-10-592, IL-10-1082, and TGFB1-509) and IL-1RN variable number of tandem repeats were genotyped. For the group without GC, intestinal metaplasia (IM) at corpus was more prevalent in GC relatives than in controls in the age of less than 50 years [grade of IM (mean±standard deviation), 0.02±0.15 in controls vs. 0.22±0.56 in GC relatives, P=0.018]. cagA, vagA s1 and m1, and oipA positives showed an increase in GC relatives among current H. pylori-infected patients, which did not reach a statistical significance. Among intestinal-type GC patients, multivariate analyses showed that residence in a rural area during childhood (odds ratio: 2.03; 95% confidence interval: 1.05-3.95) and TGFB1-509 T (odds ratio: 0.47; 95% confidence interval: 0.26-0.88) were associated with a positive family history of GC; however, it showed only insignificant results in diffuse-type GC. The intrafamilial aggregation of GC might be associated with environmental factors during childhood or TGFB1-509 genetic polymorphism, or possibly H. pylori virulence. These factors may promote IM and development of intestinal-type GC.