Gastric Carcinoma Group Research Articles

FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract

BackgroundFGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT.Patients and methodsTo assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization.ResultsTwenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005).ConclusionHomogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.

Greater expression of THBS2 and VACN in gastric carcinoma compared to gastritis.

e16026 Background: Gastric carcinoma (GC) is one of the most common cancers with the lowest survival rate in the world. The development from gastritis to GC may be related to genetic factors, but the specific molecular mechanism is not clear. The present study aimed to explore the gene difference between GC and gastritis. Methods: Two gene expression profiles including GC and gastritis were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between GC and gastritis were explored. Through pathway enrichment of DEGs, hub genes were identified. The prognosis significances of hub genes for GC patients were analyzed by overall survival (OS) analysis. Animal models of gastritis and GC were constructed and immunofluorescence and RT-PCR were used to verify the distinct expression of hub genes between the two diseases. Finally, the correlations between hub genes and GC were understood based on BP neural network. Results: A total of 62 DEGs was identified between GC and gastritis. Eight hub genes were identified, including MSLN, FGA, SPP1, THBS2, SPARC, FN1, IGFBP7 and VCAN. Except SPP1, the high expression of the other seven hub genes predicted poor OS for GC patients. In mouse model, the mRNA expression of SPP1, FN1, IGFBP7, THBS2 and VCAN were significantly higher in GC group than that in gastritis group. No matter in mouse model or in Human Protein Atlas, the protein expression of THBS2 and VCAN in GC was higher than that in gastritis. Based on the strong correlation among THBS2, VACN and GC suggested by BP neural network, it was speculated that the expression levels of THBS2 and VACN may be a predictor of GC. Conclusions: Compared with gastritis, THBS2 and VACN are highly expressed in GC. THBS2 and VACN may be potential biomarkers and therapeutic targets for GC.

Distinct clinicopathological differences between early gastric cardiac and non-cardiac carcinomas: a single-center retrospective study of 329 radical resection cases

BackgroundEarly gastric carcinoma is heterogeneous and can be divided into early gastric cardiac carcinoma (EGCC) and early gastric non-cardiac carcinoma (EGNCC) groups. At present, differences in clinicopathology remains obscure between EGCC and EGNCC fundus–corpus and antrum–angularis–pylorus subgroups, especially between EGCC with and without oesophageal invasion.MethodsIn this study, we studied 329 consecutive early gastric carcinoma radical gastrectomies with 70 EGCCs and 259 EGNCCs.ResultsCompared to the EGNCC antrum–angularis–pylorus (n = 181), but not fundus–corpus (n = 78), sub-group, EGCC showed significantly older age, lower prevalence of the grossly depressed pattern, better tumor differentiation, higher percentage of tubular/papillary adenocarcinoma, but lower frequency of mixed poorly cohesive carcinoma with tubular/papillary adenocarcinoma, and absence of lymph node metastasis (LNM) in tumors with invasion up to superficial submucosa (SM1). In contrast, pure poorly cohesive carcinoma was less frequently seen in EGCCs than in EGNCCs, but mixed poorly cohesive carcinoma with tubular/papillary adenocarcinomas was significantly more common in the EGNCC antrum–angularis–pylorus sub-group than in any other group. No significant differences were found between EGCC and EGNCC sub-groups in gender, tumor size, H. pylori infection rate, and lymphovascular/perineural invasion. EGCC with oesophageal invasion (n = 22), compared to EGCC without (n = 48), showed no significant differences in the H. pylori infection rate and oesophageal columnar, intestinal, or pancreatic metaplasia, except for a higher percentage of the former in size > 2 cm and tubular differentiation.ConclusionsThere exist distinct clinicopathologic differences between EGCC and EGNCC sub-groups; EGCC was indeed of gastric origin. Further investigations with larger samples are needed to validate these findings.

Interaction of Cyclooxygenase-2 with Helicobacter pylori Induces Gastric Chronic Nonresolving Inflammation and the Formation of Syndrome of Internal Block of Static Blood in Helicobacter pylori-Related Gastric Diseases.

Cyclooxygenase-2 (COX-2) is an inducible enzyme stimulated by various inflammatory factors (IFs). Chronic gastritis is a classic model of “inflammation-cancer transformation” and Helicobacter pylori-related gastric diseases (HPGD) are specific ones of this model. Traditional Chinese Medicine (TCM) syndromes could play a predictive role in gastric histopathological evolution. To search for early warning evidence about “inflammation-cancer transformation,” this study is about to explore interaction of COX-2 with Helicobacter pylori (Hp) in HPGD with different TCM syndromes. All included subjects underwent endoscopy and biopsy. Hp infection was detected by rapid urease test and methylene blue staining. Histopathological characteristics and COX-2 expression in gastric mucosa (GM) were, respectively, observed by hematoxylin-eosin and Elivision™ plus. SPSS 18.0 and Stata 11.0 statistical software packages were used for statistical analysis. Results of immunohistochemical staining in this study showed COX-2 expression in Hp-positive patients was stronger than that in Hp-negative ones. Spearman' analysis indicated that degrees of both Hp infection and COX-2 expression were positively correlated with those of gastric inflammation and inflammatory activity. Compared with the relative normal group, both severe dysplasia group and gastric carcinoma group had more severe Hp infection and COX-2 expression. Compared with the nonsyndrome, syndrome of internal block of static blood (IBSB) had higher scores in semiquantitative analysis of COX-2 protein expression among TCM groups. Moreover, multivariate logistics regression analysis suggested that patients with Hp infection could increase the risk of IBSB. These results indicated that COX-2 interacting with Hp could play an important role in transforming gastric chronic nonresolving inflammation into carcinoma in subjects with HPGD, as well as inducing the formation of IBSB. HPGD together with IBSB could be an early warning evidence for GM with histopathological evolution from benign to malignant.

Is Human Papillomavirus and Helicobacter pylori Related in Gastric Lesions?

Human papillomavirus (HPV), the causative agent of cervical cancer, is also suggested as a risk factor for gastric adenocarcinoma. Many infectious agents besides Helicobacter pylori have been associated with gastritis. The aim of this study was to investigate HPV DNA and genotyping HPV type 16 DNA in gastric adenocarcinoma and Helicobacter pylori gastritis cases. A hundred and six gastric adenocarcinoma and Helicobacter pylori gastritis samples and 26 controls were included. After deparaffinization by xylene, DNA extraction was performed by the phenol-chloroform-isoamyl alcohol method and 106 samples were studied with a G6PDH control kit (Eurogentec, Seraing, Belgium). Fifty-three adenocarcinoma and 43 Helicobacter pylori samples were thought to have enough tissue and were studied for HPV DNA. HPV types other than 16 and HPV type 16 DNA were detected by Real Time PCR using the L1 region. Amplifications of MY09/11 products were done by GP5+/GP6+ primers and Cyanine-5 labeled HPV DNA and HPV 16 DNA specific probe in Light Cycler 2.0 (Roche Diagnostics, Germany) device. Among gastric adenocarcinoma and Helicobacter pylori gastritis samples, 20/53 (38%) and 18/43 (41.8%) were HPV DNA positive, respectively. Five (19.2%) of 26 controls were HPV DNA positive. Our 38% positive result in the gastric carcinoma group is in concordance with previous reports. This is the first study revealing the HPV-H. pylori relationship in gastritis cases and we concluded that with regard to the nearly three-fold higher HPV DNA (41.8%) in gastritis cases compared to controls, Helicobacter pylori positive cases should also be evaluated in favor of HPV in the gastritis group.

The Relationship between Helicobacter Pylori Virulence Factors and Gastric Carcinoma

Background: Helicobacter pylori is a gram-negative microaerophilic bacterium found usually in the stomach and use several mechanisms to survive in the stomach lumen. The presence of these bacteria in the stomach can lead to gastritis and reduction in stomach acid production. Aim of the work: this study aimed to investigate the seroprevalence of six highly immunogenic virulence factors (Cag A, Vac A, Gro EL, gGT, Hcp C and Ure A) in patients with different gastric histology in a high-risk population of gastric cancer and explore the relationship between H. pylori virulence factors and gastric carcinoma. Methods: this study included 100 patients: 25 patients were diagnosed histopathologically as gastric cancer (Group I) and 75 patients were diagnosed endoscopically as mild gastritis (Group II). Their samples were collected from Military Armed Hospitals. Noninvasive serologic test was performed to detect immune responses to H. pylori by stool antigen test, ELISA and by Recomoline H. pylori test. Results: on comparing results of gastric carcinoma and chronic gastritis by Recomoline H. pylori test, it was found that Cag A was detected in 88% (22/25) in group I. While, in group II it was 57.33% (43/75) of cases and Vac A was detected in 80% (20/25) in group I while, it was in group II in 44% (33/75) of cases. Gro EL was detected in 72% (18/25) in group I while; it was 49.33% (37/75) group II and Urea A was 52% (13/25) in group I while, it was 52% (39/75) in group II. Hcp c was 56% (14/25) in group I while, it was 40% (30/75) in group II and gGT was 48% (12/25) in group I while, it was 34.67% (26/75) in group II. Conclusion: in this study, a statistically significant association was found between Cag A, Vac A and Gro EL antigen in the studied groups of patients. However, no such statistically significant association was found between Urea A, Hcp c and gGT antigen. (P value > 0.05). Thus, Cag A, Vac A and Gro EL antigen proved to be virulence markers for gastric carcinoma group.

Local Immune Response in Helicobacter pylori Infection.

There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori–infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines—interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32—in H pylori–infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori–infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.

Gastric Carcinomas in Young (Younger than 40 Years) Chinese Patients

Little is known about clinicopathological characteristics of gastric carcinoma (GC) in young (≤40 years) Chinese patients. We aimed in this study to analyze those features along with family history and prognostic factors after resection. We retrospectively reviewed all 4671 GC resections (surgical and endoscopic) performed at our center from 2004 to 2014 and identified 152 (3.2%) consecutive young patients. Patient demographics, clinical results, family history, and endoscopic-pathological findings were analyzed along with the older (>41 years) GC controls recruited in the same study period. Clinicopathological factors related to postresection outcomes were assessed statistically. The trend of GC resections in young patients was not changed over the study period. Compared to old GCs, the young GC cohort was predominant in women, positive family history, middle gastric location, the diffuse histology type, shorter duration of symptoms, and advanced stage (pIII+pIV, 53.3%). Radical resection was carried out in 90.1% (n = 137) with a better 5-year survival rate (70.3%) than palliative surgery (0%, n = 15). There was no significant difference in clinicopathological characteristics between familial GC (FGC, n = 38) and sporadic GC (SGC, n = 114) groups. Very young patients (≤ 30 years, n = 38) showed lower Helicobacter pylori (Hp) infection and significantly higher perineural invasion rates, compared to older (31-40 years) patients. Hp infection was more commonly seen in the Lauren's intestinal type and early pT stages (T1+T2). Independent prognostic factors for worse outcomes included higher serum CA 72-4, CA 125 levels, positive resection margin, and stage pIII-pIV tumors. The 5-year survival rate was significantly higher in patients with radical resection than those without. GCs in young Chinese patients were prevalent in women with advanced stages but showed no significant differences in clinicopathology between FGC and SGC groups. High serum CA 72-4 and CA 125 levels may help identify patients with worse outcomes. Radical resection improved postresection survival.

Abstract 2716: Epstein-Barr virus-encoded BARF1 downregulates SMAD4 and increases miR-146a in gastric carcinoma cells

Abstract Recently, molecular analytic data from ‘The Cancer Genome Atlas’ (TCGA) (http://www.cbioportal.org) has re-confirmed that Epstein-Barr virus (EBV)-infected gastric carcinoma is a specialized subset of gastric carcinomas. However, viral oncogene has not yet been established in gastric carcinomas. Several reports have suggested that EBV-encoded BARF1 may be a putative viral oncogene in gastric carcinoma. The aim of this study was to investigate alterations of cellular microRNA and cellular protein by BARF1 in gastric carcinoma cells. We cloned BARF1 from naturally EBV-infected gastric carcinoma cell line, and transfected BARF1 into EBV-negative gastric carcinoma cells, thus produced a stable cell line of BARF1-transfected gastric carcinoma cells. BARF1-transfected gastric carcinoma cells revealed significantly increased cellular proliferation than its original cells. The MicroRNA array (Agilent release 16.0) data and Taqman RT-PCR results showed that cellular miR-146a was highly expressed in BARF1-transfected gastric carcinoma cells, comparing to that in original cells. In BARF1-transfected gastric carcinoma cells, transfection with BARF1-siRNA offset the increment effect of miR-146. Using bioinformatics analyses for miR-146a target (RNA hybrid 2.2 and TargetScan 5.2 sites), we found that miR-146a target seed sequence existed in the 3′ UTR of SMAD4 mRNA. The Western blot assay demonstrated that SMAD4 was remarkably reduced by BARF1 transfection. When immunohistochemistry for SMAD4 was performed on 343 cases of surgically resected, human gastric carcinoma tissues, 32 (9%) EBV-infected gastric carcinoma group disclosed more frequent loss of SMAD4 than EBV-negative group. In conclusion, EBV-encoded BARF1 could promote proliferation of gastric carcinoma cells, thereby contributing to EBV-induced cancer progression, in which SMAD4 downregulation, probably through miR-146a increase, may be entailed. Citation Format: Dong Ha Kim, Chan Jin Yoon, Jin, Kyung Rho, Jaap M. Middeldorp, Jun Hee Woo, Mee Soo Chang. Epstein-Barr virus-encoded BARF1 downregulates SMAD4 and increases miR-146a in gastric carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2716. doi:10.1158/1538-7445.AM2015-2716

Toll-like receptor gene polymorphisms and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma in Northern China.

Background/Aims:Various polymorphisms in toll-like receptor (TLR) genes have been identified and associated with susceptibility to various malignancies, such as gastric carcinoma (GC), breast cancer, and prostate cancer. However, little is known about the polymorphisms of TLR genes and the susceptibility to GC in Northern China, especially to Epstein–Barr virus-associated GC (EBVaGC). We focused on the association with susceptibility to GC, especially to EBVaGC.Patients and Methods:Polymorphisms of the TLR2, 3, 4, and 9 genes were measured in 52 cases of EBVaGC and 157 cases of EBV-negative GC (EBVnGC). Ninety-four peripheral blood samples from healthy individuals were also examined.Results:For the TLR2 gene (196 to 174 del), there was no significant difference between the GC group and control group in genotype, but there was a significant difference in the del allele. As for the TLR3 gene (c. 1377C/T), there were significant differences between the GC group and the control group in both genotype and allelic frequency. No SNPs single nucleotide polymorphisms (SNPs) were found in the TLR4 gene at the sites Asp299Gly and Thr399Ile. As for TLR9 1486T/C (rs187084) and C2848T (rs352140), there was also no association between the GC group and control. In all of the indicators, there were no significant differences between EBVaGCs and EBVnGCs.Conclusions:The TLR3 gene (c. 1377C/T) polymorphisms and the del allele of the TLR2 gene (196 to 174) were both associated with susceptibility to GC in Shangdong Province of Northern China. There was no interaction between EBV and TLR gene polymorphisms in EBVaGC.

Relationships between Notch1, DLL4, HES-1 expression and angiogenesis, lymphangiogenesis of gastric carcinoma and their significances

Objective To investigate the expression of Notch1,Delta-like ligand 4 (DLL4),hairy and enhancer of split-1 (HES-1),microvessel density (MVD),lymphatic vessel density (MLD) in gastric carcinoma,so as to discuss their roles in the development of gastric carcinoma.Methods Gastric carcinoma,paracancer tissues which was apart from the edge of cancer tissue ＞ 60 mm obtained during operation and normal gastric mucosa obtained during gastroscopy were used as controls.All specimens were made tissue microarray.The expressions of Notchl,DLL4,HES-1 were detected by immunohistochemistry.Immunohistochenical double taining was used to detect MVD and MLD.The relationships between Notch1,DLL4,HES-1 expression and angiogenesis,lymphangiogenesis and their significances were analyzed.Results The positive rate of Notch1 in gastric carcinoma was 48.30％,significantly higher than that of paracancerous (25.00％,x2 =6.38,P ＜ 0.05) and control group (16.67％,x2 =10.18,P ＜0.05).The differences of the positive rate of DLL4 in gastric carcinoma (55.94％),paracancerous (45.70％) and control group (56.67％) were not significant (x2 =1.18,P ＞0.05 ; x2 =0.005,P ＞ 0.05).The differences of the positive rate of HES-1 in gastric carcinoma (36.64％),paracancerous (34.40％) and control group (33.33％) were not significant (x2 =0.05,P ＞ 0.05 ;,x2 =0.11,P ＞ 0.05).The mean of MVD in gastric carcinoma group was 28.84 ± 14.17,which was significantly higher than that in paracancerous group (17.02 ±8.54,t =4.03,P＜0.05) and control group (16.69 ±7.21,t =5.01,P＜0.05).The mean of MLD in gastric carcinoma group was 8.55 ±4.98,which was significantly higher than that in paracancerous group (4.05 ± 2.48,t =9.30,P ＜ 0.05) and control group (3.99 ± 1.56,t =10.32,P ＜ 0.05).The expression of DLL4 was correlated with MVD (t =2.77,P ＜ 0.05),but wasn't correlated with MLD (t =1.89,P ＞0.05).There were no correlations between the expression of Notch1,HES-1 and tissues MVD,MLD (P ＞0.05).Conclusion Notch1 plays important roles in the development of gastric carcinoma.There are many angiogenesis and lymphangiogenesis in gastric carcinoma.The expression of DLL4 in gastric carcinoma has certain effect in the formation of microvessel. Key words: Stomach neoplasms; Receptor, Notch1 ; Lymphatic vessels; Microvessels; DLL4; HES-1

Helicobacter pylori infection and expressions of apoptosis-related proteins p53, ASPP2 and iASPP in gastric cancer and precancerous lesions

AimsThere has been limited information about the relations between Helicobacter pylori infection and expressions of apoptosis-related proteins p53, ASPP and iASPP in gastric cancer and precancerous lesions. MethodsH. pylori in gastric mucosa were identified by W-S staining and rapid urease test. Expression of apoptosis-related proteins P53, ASPP2 and iASPP in the gastric tissues were determined by immunohistochemistry. ResultsThe concentrations of H. pylori and expressions of p53 and iASPP in gastric carcinoma group and precancerous lesion group were higher than in benign gastric diseases group (P<0.05). The expressions of ASPP2 in gastric carcinoma and precancerous lesion group were lower than in benign gastric diseases group (P<0.05). The expressions of p53 and iASPP in H. pylori positive group were higher than in H. pylori negative group (P<0.05), whereas ASPP2 in H. pylori positive group were lower than in H. pylori negative group (P<0.05). ConclusionThere was a higher rate H. pylori infection, an increased expression of apoptosis inhibitor iASPP, and decreased expression of apoptosis stimulator ASPP2 in gastric cancer or precancerous tissues. These results suggest that H. pylori may cause gastric cancer by up-regulating iASPP and down-regulating ASPP2.

Missed synchronous gastric neoplasm with endoscopic submucosal dissection for gastric neoplasm: Experience in our hospital

Endoscopic submucosal dissection (ESD) has been widely accepted as a less invasive treatment for early gastric cancer and adenoma, but research on missed synchronous gastric neoplasm (SGN) with ESD has been limited. In the present study, we aimed to investigate the incidence and characteristics of missed SGN during follow-up endoscopy in patients who have undergone ESD. We investigated the clinicopathological features of 602 patients and gastric neoplasms treated by ESD from January 2005 through July 2009 at our institution. We defined any second neoplasm found within 1 year after ESD as a missed SGN. Out of 602 patients, 12 (2.0%) had missed SGN. Among the 12 missed SGN, seven (58.3%) cases were carcinomas. All cases of missed synchronous gastric cancer (SGC) were exclusively discovered in the posterior wall of the stomach (7 of 7 cases, 100%, P = 0.016). Missed SGN were more frequently observed when the primary gastric neoplasm was adenoma (4.0% vs 1.0%; OR = 4.114; 95% CI = 1.224-13.831). Furthermore, the risk of missed SGC increased 12-fold in the primary gastric adenoma group compared to the primary gastric carcinoma group (2.9% vs 0.24%; OR = 12.308; 95% CI = 1.472-102.939). Endoscopists need to make an effort to find SGN, especially when they carry out ESD for an adenoma, which is a less serious lesion. The important blind spot in screening endoscopic examination before ESD is the posterior wall of the upper third and middle third of the stomach.

Oxidative DNA damage and repair in chronic atrophic gastritis and gastric cancer.

Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to gastric carcinogenesis. The aim of this research was to detect the 8-OHdG and the expression of hOGG1and MnSOD, in human gastric mucosa with chronic atrophic gastritis (CAG) and gastric carcinoma (GC) comparing with normal controls (NC). The level of 8-OHdG in gastric biopsy specimens was assessed with immunohistochemistry. The expression level of hOGG1and MnSOD in gastric tissues was assessed with Western blot. The 8-OHdG staining in CAG and GC mucosa was stronger than control (p<0.01). hOGG1 was expressed to a lower degree in GC and CAG when compared to the control group (both p<0.01) and the level of GC was even lower than CAG (p<0.05). MnSOD was expressed to a greater degree in GC group when compared to the control (p<0.05). CAG patients who express 8-OHdG highly should be monitored for the potentially occurrence of GC. The lower lever of hOGG1 in CAG and GC with higher level of 8-OHdG implies that hOGG1 is closely related to oxidative DNA damage and may lead to carcinoma. The increasing expression of MnSOD in the gastric mucosa may indicate the occurrence of gastric cancer.

The relationship between the expression of bFGF in gastric cancer and precancerous lesions

Objective To explore the relationship of bFGF in the pathogenesis of gastric cancer.Methods The expression of bFGF was determined by immunohistochemical method in 130 gastric specimens including 30 cases of chronic superficial gastritis,30 cases of intestinal metaplasia,30 cases of dysplasia and 40 cases of gastric carcinomas.Results In control group with chronic superficial gastritis,precancerous group,and gastric carcinoma group,the expression level of bFGF had a increasing tendency(P ＜ 0.05).Conclusion The expression of bFGF was up-regulated in the carcinogenesis of gastric carcinoma. Key words: Stomach neoplasms; Fibroblast growth factor-2

DNA methylation of microRNA-34b/c and microRNA-124a in gastric cancer

To explore the effects of DNA methylation of microRNA (miRNA) gene on their expressions in patients with gastric carcinoma. A total of 80 subjects were divided into gastric carcinoma group (n = 40) and control group (n = 40). The DNA methylation status of miRNA-34b/c and miRNA-124a gene promoters was detected by DNA methylation specific polymerase chain reaction (MSP) in gastric carcinoma tissues and normal mucosal tissues. The positive rate of DNA methylation of miRNA-34b/c gene promoter was 77.5% (31/40) and 5.0% (2/40) in gastric carcinoma and control groups respectively. There was statistically significant difference between two groups (P < 0.05). The positive rate of DNA methylation of miRNA-124a gene promoter was 60.0% (24/40) and 0 in these two groups respectively. There was statistically significant difference between two groups (P < 0.05). Also the hypermethylation positivity of gene promoter of miRNAs was correlated with the clinicopathological features of gastric carcinoma. The hypermethylation of miRNA-34b/c and miRNA-124a gene promoters may play a crucial role in the occurrence and development of gastric carcinoma.

Expression and prognostic significance of gastric‐specific annexin A10 in diffuse‐ and intestinal‐type gastric carcinoma

Annexin A10 (ANXA10) and its liver-specific short isoform (ANXA10S) had tissue-restricted expression. The downregulation of ANXA10S is correlated with tumor progression and poor prognosis in hepatocellular carcinoma. The aim of the present study was to validate the tissue distribution and explore the role of the ANXA10 protein expression in gastric carcinoma. We examined the ANXA10 protein expression in human and animal tissues and 356 resected primary gastric carcinomas, using specific mouse and rabbit polyclonal antibodies, by immunohistochemical staining. The ANXA10 protein is a nuclear protein specifically expressed in fetal and adult gastric mucosa and Brunner's gland across species, including humans, minipigs, woodchucks, and mice, and is commonly lost in gastric mucosa with intestinal metaplasia. The ANXA10 protein was expressed in 43.5% (155 cases) of gastric carcinomas; 74.2% (98/132) in the diffuse-type gastric carcinoma (DGC), 73.7% (28/38) in the mixed-type gastric carcinoma, and significantly lower in the intestinal-type gastric carcinoma (IGC) and indeterminate groups, 16.8% (28/167) and 5.3% (1/19), respectively (P<1×10(-8)). IGC with ANXA10 expression was correlated with a higher stage (P=0.049), particularly higher in stage IIIA/IIIB/IV IGC than lower-stage (IA/IB/II) tumors (P=0.005), but was not correlated with age, sex, and nodal status. In contrast, DGC with ANXA10 expression was associated with younger age, female patients, and importantly, lower tumor stage and lymph node metastasis (P=0.007, P=0.065, P=0.024, and P=0.0014, respectively). Moreover, DGC with ANXA10 expression had a better 5-year patient survival (P=0.0048), whereas IGC with ANXA10 expression had a lower 5-year survival (P=0.034). The ANXA10 protein expression is a novel marker of gastric differentiation, and is differentially expressed in IGC and DGC, with opposite prognostic significance.

Correlation of polymorphism of Nme1-1465 T>C and TGFβ1-509 T>C with genetic susceptibility of gastric carcinoma

To explore the correlation of functional genetic variants in Nme1-509 C>T and TGFβ1-1465 T>C genes to the genetic susceptibility of gastric carcinoma in Fujian province, China. A case-control study was conducted in a population in Fujian province. The polymorphism of TGFβ1-509 C>T (rs1800469), Nme1-1465 T>C (rs16949649) in 273 gastric carcinoma patients and 277 cancer-free controls, frequency-matched by age and sex, were analysed by using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Adjusted odds ratios (OR) and 95% confidence evaluation intervals (95%CI) measured by multivariate Logistic regression analysis were adopted in studying the correlation of the gene polymorphism with the susceptibility of gastric cancer. After the adjustment using Logistic regression or the potential confounding effects of gender and age, as compared with TT+CT genotype gastric carcinoma patients, the homozygous Nme1-1465CC genotype carriers had a significantly higher risk in lymph node metastasis, with the OR of 2.5 (95%CI 0.08-2.10; P=0.029). There was no association obtained between TGFβ1-509 T>C genotype with the tumor size, cell differentiation, tumor invasion and lymph node metastasis in gastric carcinoma. In the intestinal type gastric carcinoma group, when compared with the wild homozygous Nme1 TT* TGFβ1 CC, Nme1 TC* TGFβ1 TC, Nme1 TC* TGFβ1 TT and Nme1 CC* TGFβ1 TC genotype carriers, there was a significantly decrease of risk in gastric carcinogenesis of 0.42 fold (95%CI 0.54-0.94, P=0.022), 0.32 fold (95%CI 0.42-0.97, P=0.013) and 0.26 fold (95%CI 0.42-0.97, P=0.008), respectively. There is a significant relationship between polymorphism of Nme1-1465 T>C and the prognosis of carcinoma of stomach. It also demonstrates that coexistence of Nme1-1465 T>C and TGFβ1-509 T>C genes may provide a synergistic effect of increasing the susceptibility of gastric carcinogenesis.

Genetic polymorphisms of metabolic enzymes—CYP1A1, CYP2D6, GSTM1, and GSTT1, and gastric carcinoma susceptibility

Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. In this study, the relationships between genetic polymorphisms of phase I metabolic enzymes including cytochrome P450 1A1 (CYP1A1), CYP2D6 and phase II metabolic enzymes such as glutathione S-transferase M1 (GSTM1) and GSTT1 and gastric carcinoma susceptibility were investigated. Genomic DNA was isolated from the peripheral blood of 129 healthy controls and 123 gastric carcinoma patients from Han ethnic group of Hunan Province located in Central South China. The genetic polymorphisms of the above mentioned enzymes were analyzed using PCR-RFLP techniques. There was no significant difference among the frequencies of CYP1A1 and/or CYP2D6 gene's wild type, heterozygous or homozygous mutations between the gastric carcinoma group and control group. But the differences among the frequencies of GSTM1 and GSTT1 null genotype between the gastric carcinoma and control group were significant (both P < 0.05). Also there were significant differences in the frequencies of GSTM1 null in high/high-middle differentiated, middle differentiated, middle-low differentiated and low differentiated gastric tumor separately. GSTM1 null showed an increased risk in middle-low differentiated and low differentiated gastric carcinoma type, but GSTT1 null was not a risk factor for the four pathological types of gastric carcinoma mentioned above. We report here that the genotypes of CYP1A1 and CYP2D6 are not associated with gastric carcinoma risk; GSTM1 null, but not GSTT1 null inheritably increases risk of some pathological types of gastric carcinoma in Han ethnic population of Hunan Province.

Saliva protein comparative proteomics in patients with gastric cancer

Objective To screen the saliva proteins associated with the gastric carcinoma using a comparative proteomic approach.Methods 2-DE wag applied to separate the whole saliva proteins in gas-tric cancer and paired normal group.The proteins with statistically significant differential expression be-tween the gastric carcinoma and normal groups were identified by matrix-assisted laser desorption/ionization tandem time-of-flisat mass spectrometry(MALD I-TOF-TOF-MS).Western blotting Was performed to ex-amine the differential expression of the candidate proteins.Results Fifteen protein spots were found as differentially expressed proteins,in which 9 proteins were identified successfully.Among the identified pro-teins,three were over-expressed and six under-expressed in whole saliva of gastric cancer patients as com-pared with normal group.GDP-dissociation inhibitor-2 wag found to be over-expressed in saliva of gastric cancer patients in comparison with the normal group,as confirmed by Western blotting.Conclusion Comparative proteomics analysis provides effective approach to screen the special biological markers in saliva for gastric cancer patients. Key words: Pmteomics; Gastric carcinoma; Saliva