Increased 5-hydroxymethylcytosine is a favorable prognostic factor of Helicobacter pylori-negative gastric cancer patients.

BACKGROUND: Most gastric cancer (GC) patients are diagnosed at middle or late stage because the symptoms in early stage are obscure, which causes higher mortality rates of GC. Helicobacter pylori (H. pylori) was identified as a class I carcinogen and leads to aberrant DNA methylation/hydroxymethylation. 5-hydroxymethylcytosine (5-hmC) plays complex roles in gene regulation of tumorigenesis and can be considered as an activating epigenetic mark of hydroxymethylation. AIM: To explore the association between 5-hmC levels and the progression and prognosis of GC patients with or without H. pylori infection. METHODS: A retrospective cohort study was conducted to estimate the predicted value of 5-hmC level in the progression and prognosis of GC patients with different H. pylori infection status. A total of 144 GC patients were recruited. RESULTS: The levels of 5-hmC were significantly decreased in tumor tissues (0.076 ± 0.048) compared with the matched control tissues (0.110 ± 0.057, P = 0.001). A high level of 5-hmC was an independent significant favorable predictor of overall survival in GC patients (hazard ratio = 0.61, 95% confidence interval: 0.38-0.98, P = 0.040), the H. pylori-negative GC subgroup (hazard ratio = 0.30, 95% confidence interval: 0.13-0.68, P = 0.004) and the GC patients with TNM stage Ⅰ or Ⅱ (hazard ratio = 0.32, 95% confidence interval: 0.13-0.77, P = 0.011). CONCLUSION: Increased 5-hmC is a favorable prognostic factor in GC, especially for H. pylori-negative subgroups.

Response to 'Cesarean section or non-breastfeeding for prevention of MTCT - Beware of sending the wrong message'.

We are glad to respond to the concerns of Drs. Levy and Terrault about our articles on the mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in HBeAg-positive mothers. We agree with Drs. Levy and Terrault that antiviral therapy of HBV during pregnancy could effectively decrease the MTCT, and this strategy has been recommended by WHO for pregnant women with a high viral load. However, the long-term influences of the abrupt cessation of antiretroviral drugs in mothers and prenatal exposure to antiviral drugs in newborns are not completely understood and are still under investigation. And not all pregnant mothers would accept this regiment due to the medication availability and individual willingness. It makes sense to study the influential factors on MTCT among mothers with high-risk transmission but not taking antiviral drugs. Despite the relatively large number of subjects included in our cohort (N = 857), post hoc power computation shows that the test efficacy is far from adequate to detect the association between delivery mode or feeding type and HBV MTCT. Therefore, we summarized the relevant studies to reach a relatively reasonable conclusion in HBsAg- and HBeAg-positive pregnant mothers not taking antiviral drugs. We provide an alternative option for HBsAg- and HBeAg-positive pregnant mothers who cannot access or defer to antiviral therapy during pregnancy to reduce the risk of HBV transmission to their offspring.

The role of caesarean section and nonbreastfeeding in preventing mother-to-child transmission of hepatitis B virus in HBsAg-and HBeAg-positive mothers: results from a prospective cohort study and a meta-analysis.

The study aimed to assess whether caesarean section and nonbreastfeeding can prevent mother-to-child transmission (MTCT) in HBsAg- and HBeAg-positive mothers via a cohort study and a meta-analysis. (1) Pregnant women who were positive for HBsAg and HBeAg and did not receive antiviral treatment during pregnancy were recruited from the First Hospital of Jilin University, Maternal and Child Health Care Center of Jiangsu and Henan from August 2009 to June 2015. Infants received active and passive immunity. (2) In addition, a systematic literature search was performed in the PubMed, Embase, Cochrane, China National Knowledge Infrastructure and Wanfang Chinese databases. The retrieval strategy was [("HBV" or "hepatitis b" or "hepatitis b virus") and ("mother-to-infant transmission" or "vertical transmission")]. Studies were screened, and data were extracted. The fixed-effect model was used to analyse the studies. A total of 852 mothers and 857 newborns were enrolled. At the age of 7 months, 41 infants (4.78%) were positive for HBsAg. Multivariate analysis showed that mothers with higher HBV DNA levels (>108  IU/mL; RR = 3.03, 95% CI: 1.41-6.52) were associated with an increased risk of infection. Although there was no statistical significance, caesarean section (RR = 0.61) and nonbreastfeeding (RR = 0.88) showed a tendency to reduce the risk of infection. (2) A total of 5726 studies were identified. Together with our study, 13 were included in the analysis of delivery mode, and 12 were included in the analysis of feeding mode. The risk of infection in the caesarean section group was lower than that in the vaginal delivery group (RR = 0.58, 95% CI: 0.46-0.74). In the analysis of feeding mode, the risk in the nonbreastfeeding group was significantly lower (RR = 0.74, 95% CI: 0.56-0.98). In conclusion, caesarean section and nonbreastfeeding reduced the risk of MTCT in infants of HBsAg- and HBeAg-positive mothers who did not receive antiviral therapy during pregnancy.

Single-nucleotide polymorphisms in Toll-like receptor genes are associated with the prognosis of gastric cancer and are not associated with Helicobacter pylori infection.

Toll-like receptors (TLRs) mediate the recognition of Helicobacter pylori (H. pylori) and initiate the innate immune response to infection. Genetic polymorphisms of TLRs play important roles in gastric carcinogenesis. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in TLR genes and H. pylori infection in the prognosis of gastric cancer (GC). A total of 756 GC patients were included in this study. Nine SNPs (TLR2: rs3804100, rs7696323, and rs10116253; TLR4: rs10983755, rs11536878, rs1927914, and rs7873784; TLR5: rs5744174; and TLR9: rs187084) in TLR genes were genotyped by MassARRAY assay. Kaplan-Meier survival curves and Cox regression were employed to conduct the associations between SNPs in TLRs and the survival of GC. Multivariate Cox regression indicated that patients with the TLR2 rs3804100 TT genotype exhibited worse survival than those with the CC + CT genotype (HR = 1.262, 95% CI: 1.006-1.582). No significant interaction between rs3804100 and H. pylori infection was observed for the prognosis of GC. Our results suggested that the TLR2 rs3804100 polymorphism may be a potential prognostic biomarker for GC independent of the H. pylori infection-related pathway.

Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

BACKGROUND: The lethal-7 (let-7) family members and their targets are involved in the development and progression of tumors. Let-7-related polymorphisms have been reported to be associated with tumorigenesis and prognosis. In gastric cancer, however, the related studies are limited. AIM: To investigate the role of let-7-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population. METHODS: A total of 898 gastric cancer patients and 992 tumor-free controls were recruited into this study from 2008 to 2013. Gastric cancer patients were followed periodically. Ten single nucleotide polymorphisms (SNPs) in the let-7 gene region or their target mRNAs were genotyped using the MassARRAY system and their associations with the risk for or overall survival of gastric cancer were analyzed. RESULTS: All the ten SNPs were in Hardy-Weinberg equilibrium. The C allele of the rs3811463 polymorphism in the 3'-untranslated region (UTR) of LIN28A was associated with a lower risk of gastric cancer [odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.61-0.88, P = 0.001] after adjustment for age and Helicobacter pylori status. Seven hundred and thirty-five gastric cancer patients who had undergone radical tumorectomy were included in the survival analysis and their 5-year survival rate was 53.9% (95%CI: 50.1%-57.6%). The rs10889677 in the 3'-UTR of IL23R was corresponded to the prognosis of gastric cancer in a dose-response manner, in which the death risk increased by 25% [hazard ratio (HR) = 1.25, 95%CI: 1.04-1.45, P = 0.011] with each increase in the number of C alleles after controlling for other potential clinicopathological parameters. CONCLUSION: The let-7-related polymorphism rs3811463 in LIN28A is associated with the susceptibility to gastric cancer and the let-7-related polymorphism rs10889677 in IL23R is associated with the prognosis of gastric cancer.

Preoperative lymphocyte-to-monocyte ratio (LMR) could independently predict overall survival of resectable gastric cancer patients.

Preoperational hemogram parameters have been reported to be associated with the prognosis of several types of cancers. This study aimed to investigate the prognostic value of hematological parameters in gastric cancer in a Chinese population. A total of 870 gastric cancer patients who underwent radical tumorectomy were recruited from January 2008 to December 2012. Preoperative hematological parameters were recorded and dichotomized by time-dependent receiver operating characteristic curves. The survival curves of patients stratified by each hematological parameter were plotted by the Kaplan-Meier method and compared by log-rank test. Multivariate Cox proportional hazards models were used to select parameters independently correlated with prognosis. The median age of the patients was 60 years. The median follow-up time was 59.9 months, and the 5-year survival rate was 56.4%. Results from the univariate analyses showed that low lymphocyte count (<2.05 × 10/L), high neutrophil-to-white blood cell ratio (NWR > 0.55), low lymphocyte-to-white blood cell ratio (LWR < 0.23), low lymphocyte-to-monocyte ratio (LMR < 5.43), high neutrophil-to-lymphocyte ratio (NLR > 1.44), and high platelet-to-lymphocyte ratio (PLR > 115) were associated with poor survival of gastric cancer patients. Multivariate analysis showed that low LMR (HR: 1.49, 95% CI: 1.17-1.89, P = .001) was the only hematological factor independently predicting poor survival. These results indicate that preoperational LMR is an independent prognostic factor for patients with resectable gastric cancer.

Randomized controlled trial of uncut Roux-en-Y vs Billroth II reconstruction after distal gastrectomy for gastric cancer: Which technique is better for avoiding biliary reflux and gastritis?

AIM: To identify which technique is better for avoiding biliary reflux and gastritis between uncut Roux-en-Y and Billroth II reconstruction. METHODS: A total of 158 patients who underwent laparoscopy-assisted distal gastrectomy for gastric cancer at the First Hospital of Jilin University (Changchun, China) between February 2015 and February 2016 were randomized into two groups: uncut Roux-en-Y (group U) and Billroth II group (group B). Postoperative complications and relevant clinical data were compared between the two groups. RESULTS: According to the randomization table, each group included 79 patients. There was no significant difference in postoperative complications between groups U and B (7.6% vs 10.1%, P = 0.576). During the postoperative period, group U stomach pH values were lower than 7 and group B pH values were higher than 7. After 1 year of follow-up, group B presented a higher incidence of biliary reflux and alkaline gastritis. However, histopathology did not show a significant difference in gastritis diagnosis (P = 0.278), and the amount of residual food and gain of weight between the groups were also not significantly different. At 3 mo there was no evidence of partial recanalization of uncut staple line, but at 1 year the incidence was 13%. CONCLUSION: Compared with Billroth II reconstruction, uncut Roux-en-Y reconstruction is secure and feasible, and can effectively reduce the incidence of alkaline reflux, residual gastritis, and heartburn. Despite the incidence of recanalization, uncut Roux-en-Y should be widely applied.

Polymorphisms of cancer stem cell marker gene CD133 are associated with susceptibility and prognosis of gastric cancer.

AIM: This study was aimed to investigate the associations between single nucleotide polymorphisms of cancer stem cell marker genes, CD44 and CD133, and susceptibility and prognosis of gastric cancer. PATIENTS & METHODS: Five single nucleotide polymorphisms in CD44 and CD133 genes were genotyped in 898 gastric cancer cases and 992 controls. RESULTS: The A/C or C/C genotypes of CD133 rs2240688 were associated with decreased risk of gastric cancer comparing with the A/A genotype (odds ratio: 0.81; 95% CI: 0.67-0.97; p = 0.023). The T allele of CD133 rs3130 predicted a worse survival for gastric cancer patients receiving tumorectomy (hazard ratio: 1.28; 95% CI: 1.04-1.58; p = 0.020), independent from tumor node metastasis stage, vessel invasion and postoperational chemotherapy. CONCLUSION:  CD133 polymorphisms are promising biomarkers for genetic susceptibility and prognosis prediction of gastric cancer.

Protective effect of an improved immunization practice of mother-to-infant transmission of hepatitis B virus and risk factors associated with immunoprophylaxis failure.

Although routine immunoprophylaxis has been known to reduce hepatitis B virus (HBV) transmission, immunoprophylaxis failure still occurs. The study aimed to investigate the protective efficacy of an improved immunoprophylaxis protocol to prevent mother-to-infant transmission of HBV and to explore the potential risk factors associated with immunoprophylaxis failure and low antibody response.A prospective observational cohort study was conducted from July 2012 to April 2015. A total of 863 HBsAg-positive mothers and their 871 infants (8 pairs of twins) were included in the study. Two different hepatitis B vaccine doses (20 or 10 µg) were administered to the infants based on the hepatitis B e-antigen (HBeAg) status of their mothers. Simultaneously, hepatitis B immunoglobulin (HBIG) was administered to the infants. Initial injections of HBIG and the hepatitis vaccine were given within 2 hours after birth. Rates of HBV infections among the infants were evaluated at 7 months of age. Factors associated with immunoprophylaxis failure and low responses to vaccination were analyzed by unconditional logistic regression..At 7 months of age, no immunoprophylaxis failure was observed in the 565 infants born to HBeAg-negative mothers. Among the 306 infants born to HBeAg-positive mothers, immunoprophylaxis failed in 16 infants (5.2%) of the infants and they were found to be HBsAg-positive. Further analysis showed that HBV DNA levels ≥10 IU/mL [odds ratio (OR) = 4.53, 95% confidence interval (95% CI): 1.19-17.34], delayed vaccination (OR = 4.14, 95% CI: 1.00-17.18), and inadequate initial injections (OR = 7.69, 95% CI: 1.71-34.59) were independently associated with immunoprophylaxis failure. Adequate titers of antibody to HBsAg (anti-HBs, ≥100 mIU/mL) were present in 96.5% of immunoprophylaxis-successful infants. For full-term infants, birth weights <3000 g were correlated with low immune responses to vaccination.This improved immunoprophylaxis protocol is effective in preventing perinatal transmission of HBV. Among infants with HBeAg-positive mothers, high HBV viral loads and inadequate and delayed initial injections were associated with immunoprophylaxis failure. The majority of the infants in our study produced adequate levels of protective anti-HBs titers after immunoprophylaxis. Additional efforts to further reduce perinatal transmission should be considered, especially for HBeAg-positive mothers.

Association of the miR-146a rs2910164 polymorphism with gastric cancer susceptibility and prognosis.

AIM: Single nucleotide polymorphisms in miRNA-coding region may be involved in the development or progression of gastric cancer (GC). MATERIALS & METHODS: Six SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-27a rs895819, miR-423 rs6505162, miR-608 rs4919510, miR-149 rs2292832) were genotyped in 898 histologically confirmed GC cases and 992 controls in this hospital-based case-control study. RESULTS: The G/G genotype of rs2910164 was associated with reduced risk of GC (odds ratio: 0.76, 95% CI: 0.60-0.97; p = 0.024). Meanwhile, in 838 GC cases receiving radical tumorectomy, cases bearing the G/G genotype of rs2910164 had shorter survival time comparing to cases with C/C or C/G genotype (hazard ratio: 1.36, 95% CI: 1.04-1.78, p = 0.023). CONCLUSION: rs2910164 of miR-146a is associated with GC.

Interaction between Helicobacter pylori and host genetic variants in gastric carcinogenesis.

Helicobacter pylori (H. pylori) is the definite carcinogen of gastric cancer. H. pylori infection induces chronic inflammation, causes DNA damage and aberrant methylation of genes and these pathways are involved in H. pylori-related gastric carcinogenesis. Polymorphisms of the genes involved in these pathways could alter susceptibility to gastric cancer. In this mini review, we focused on the role of polymorphisms in these genes on the susceptibility to gastric cancer, with a particular emphasis on their possible interactions with H. pylori infection. We found that many studies on this theme did not simultaneously report H. pylori infection and the interactions remained inconclusive.

CD24 genetic variants contribute to overall survival in patients with gastric cancer.

AIM: To investigate the role of single nucleotide polymorphisms (SNPs) in CD24 gene in susceptibility and overall survival of gastric cancer (GC). METHODS: We genotyped 3 tagging SNPs of CD24-P-534 in the promoter region, P170 in the coding region of exon 2 and P1527 in the 3' untranslated region - using polymerase chain reaction-restriction fragment length polymorphism in specimens from 679 histologically-confirmed GC cases, 111 gastric atrophy (GA) cases and 976 tumor-free controls. Serum immunoglobulin G antibodies to Helicobacter pylori (H. pylori) of all subjects were detected by enzyme-linked immunosorbent assay. CD24 expression was evaluated by immunohistochemistry in 131 GC specimens. Correlations between SNPs and risk of GC or GA were shown by P values and odd ratios (ORs) with 95% confidence intervals (95%CI) compared with the most common genotype of each SNP using the unconditional logistic regression model after adjusting for age, sex and H. pylori infection. Survival within each SNP group was plotted by Kaplan-Meier method and compared by log-rank test (recessive model). Hazard ratios with 95%CIs were computed by Cox regression model after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy. RESULTS: All of the three loci were in Hardy-Weinberg equilibrium in the control group. Median follow-up time for the 600 GC patients included in the survival analysis was 36.2 mo (range, 2.1-66.7 mo; 95%CI: 34.3-36.5 mo). Patients with the P-534 A/A genotype had significantly shorter survival (HR = 1.38, 95%CI: 1.01-1.88, P = 0.042) than did the C/C or C/A genotype carriers after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy. This trend was more evident in patients who lived longer than 2.5 years (HR = 7.55, 95%CI: 2.16-26.32, P = 0.001). The P170 T/T genotype was associated with a shorter lifespan than the non-T/T genotypes, but not significantly so. None of the three genetic variants was found to be associated with risk of GC (including tumor stage, grade and distant metastasis) or with risk of gastric atrophy. Furthermore, no difference of CD24 expression was found among the genotypes. CONCLUSION: The P-534 site in CD24 gene affects the overall survival of gastric cancer and may serve as a prognostic marker for gastric cancer.

DNA methyltransferase3a expression is an independent poor prognostic indicator in gastric cancer.

AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value. METHODS: From April 2000 to December 2010, 227 men and 73 women with gastric cancer were enrolled in the study. The expression of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a and DNMT3b, in the 300 cases of gastric carcinoma, of which 85 had paired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray. Serum anti-Helicobacter pylori (H. pylori) IgG was detected by enzyme-linked immunosorbent assay (ELISA). The relationships between the above results and the clinicopathological characteristics were analyzed. Their prognostic value was evaluated using the Cox proportional hazards model. RESULTS: In gastric cancer, expression of DNMTs was mainly seen in the nucleus. Weak staining was also observed in the cytoplasm. Expression of DNMT1, DNMT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples (60.0% vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01). The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients (Log-rank test, P = 0.032). No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time (Log-rank test, P = 0.289, P = 0.347). Multivariate regression analysis indicated that DNMT3a expression (P = 0.025) and TNM stage (P < 0.001), but not DNMT1 (P = 0.54) or DNMT3b (P = 0.62), were independent prognostic factors in gastric cancer. H. pylori infection did not induce protein expression of DNMTs. CONCLUSION: The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer. DNMT3a might play an important role in gastric carcinogenesis.

DNMT3a rs1550117 polymorphism association with increased risk of Helicobacter pylori infection.

BACKGROUND: DNA methyltransferase-3a (DNMT3a) plays significant roles in embryogenesis and the generation of aberrant methylation in carcinogenesis. This study aimed to investigate associations between single nucleotide polymorphisms (SNPs) of the DNMT3a gene and risk of Helicobacter pylori infection, gastric atrophy and gastric cancer. METHODS: The subjects comprised 447 patients with gastric cancer; 111 individuals with gastric atrophy and 961 healthy controls. Two SNPs (rs1550117 and rs13420827) of the DNMT3a gene were genotyped by Taqman assay. DNMT3a expression was analyzed in cancer tissues from 89 patients by tissue microarray technique. Odds ratio (ORs) and 95% confidence intervals were calculated by multivariate logistic regression. RESULTS: Among healthy controls, risk of H.pylori infection was significantly higher in subjects with the rs1550117 AA genotype, compared to those with GG/AG genotypes of DNMT3a [OR=2.08, (95%CI: 1.02-4.32)]. However, no significant correlation was found between the two SNPs and risk of developing gastric atrophy or gastric cancer. In addition, no increase in DNMT3a expression was observed in the gastric cancer with H.pylori infection. CONCLUSIONS: This study revealed that DNMT3a rs1550117 polymorphism is significantly associated with an increased risk of H. pylori infection, but did not support any evidence for contributions of DNMT3a rs1550117 and rs13420827 to either gastric atrophy or gastric cancer. The biological roles of DNMT3a polymorphisms require further investigation.

Anticancer effects of 4-vinyl-2,6-dimethoxyphenol (canolol) against SGC-7901 human gastric carcinoma cells.

Gastric cancer remains the fourth most commonly diagnosed cancer and is the second leading cause of cancer-related mortality worldwide. The aim of this study was to investigate the effects of canolol on the proliferation and apoptosis of SGC-7901 human gastric cancer cells and its relevant molecular mechanisms. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to observe the effect of canolol on the proliferation of SGC-7901 human gastric adenocarcinoma cells. The results showed that SGC-7901 cells exhibited a marked dose-dependent reduction in the proliferation rate. The survival rate of the cells was 88.86±1.58% at 50 µmol/l, decreasing to 53.73±1.51% at 800 µmol/l (P<0.05). By contrast, canolol had no significant toxicity on the human gastric mucosal epithelial cell line GES-1. The vivid images of cell morphology using an inverted microscope provided confirmation of the MTT assay. Treatment of SGC-7901 cells with canolol resulted in apoptosis demonstrated by flow cytometry. Furthermore, canolol downregulated the mRNA levels of COX-2, but had no significant effect on the mRNA expession of the Bax and Bcl-2 genes. These findings suggest that canolol has potential to be developed as a new natural anti-gastric carcinoma agent.

Polymorphisms of PTPN11 gene could influence serum lipid levels in a sex-specific pattern.

BACKGROUND: Previous studies have reported that different genotypes of PTPN11 gene (protein tyrosine phosphatase, non-receptor 11) were associated with different levels of serum lipids. The aim of this study was to explore the relationship between single nucleotide polymorphisms (SNPs) of PTPN11 and serum lipids in Northeast Chinese. METHODS: A total of 1003 subjects, 584 males and 419 females, were included in the study and their serum lipids were determined. Five htSNPs (rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860) of PTPN11 gene were genotyped using TaqMan assay method. RESULTS: All of the five SNPs were in Hardy-Weinberg equilibrium. The male subjects had higher triglyceride (TG), higher low-density lipoprotein cholesterol (LDL-C) and lower high-density lipoprotein cholesterol (HDL-C) level than females. In males, rs4767860 was found to be associated with serum TG and total cholesterol (TC) levels and rs12229892 was associated with TC level. However, these significant associations could not be observed in females. In females, rs2301756 was found to be associated with TG and rs7958372 was associated with LDL-C level. Haplotype analysis showed that the GCGTG haplotype was associated with slightly higher TG level and ATGCG with higher TC level. CONCLUSIONS: SNPs of PTPN11 may play a role in serum lipids in a sex-specific pattern. However, more studies are needed to confirm the conclusion and explore the underlying mechanism.

Increased expression of tyrosine phosphatase SHP-2 in Helicobacter pylori-infected gastric cancer.

AIM: To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values. METHODS: Three hundred and five consecutive cases of gastric cancer were enrolled into this study. SHP-2 expression was carried out in 305 gastric cancer specimens, of which 83 were paired adjacent normal gastric mucus samples, using a tissue microarray immunohistochemical method. Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes. Serum anti-Helicobacter pylori (H. pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay. Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients. RESULTS: SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells. Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively (P < 0.001). Though SHP-2 staining intensities were stronger in the H. pylori (+) group than in the H. pylori (-) group, no statistically significant difference was found in the expression levels of SHP-2 between H. pylori (+) and H. pylori (-) gastric cancer (P = 0.40). The SHP-2 expression in gastric cancer was not significantly associated with cancer stages, lymph node metastases, and distant metastasis of the tumors (P = 0.34, P = 0.17, P = 0.52). Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival (P = 0.86). CONCLUSION: Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant up-regulation of SHP-2 protein might play an important role in the gastric carcinogenesis.

Association of polymorphism of PTPN 11 encoding SHP-2 with gastric atrophy but not gastric cancer in Helicobacter pylori seropositive Chinese population.

BACKGROUND: The interaction between Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2) of gastric epithelial cells and cagA from H. pylori plays a crucial role in developments of gastric atrophy and gastric cancer. This study aimed to investigate the association of haplotype tagging SNPs (htSNPs) in the PTPN11 gene encoding SHP-2 with gastric atrophy and gastric cancer in Chinese population. METHODS: The subjects comprised 414 patients with gastric cancer, 109 individuals with gastric atrophy and 923 healthy controls. Blood was collected from October 2008 to October 2010. Five htSNPs rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860 from the PTPN11 gene were selected and genotyped by Taqman assay. Serum Ig G antibodies to H. pylori were detected by ELISA. Gastric atrophy was screened by the levels of serum pepsinogenIandII, and confirmed by endoscopy and histopatholgical examinations. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by a multivariate logistic regression. RESULTS: Among H. pylori seropositive subjects, age and gender-adjusted OR of gastric atrophy was 2.47 (95%CI 1.13-4.55, P = 0.02) for CC genotype compared with CT/TT genotypes, suggesting a recessive model of genetic risk for rs12423190. The prevalence of H. pylori seropositivity were significantly higher in groups of gastric cancer and gastric atrophy compared to the control group (70.3% vs. 75.2% vs. 49.7%, P <0.001). However, the distributions of genotypes and haplotypes in patients with gastric cancer were not significantly different from healthy controls. CONCLUSIONS: Our study provides the first evidence that rs12423190 polymorphism of the PTPN11 gene is significantly associated with an increased risk of gastric atrophy in H. pylori infected Chinese Han population, suggesting that rs12423190 polymorphism could be used as a useful marker of genetic susceptibility to gastric atrophy among H. pylori infected subjects. The biological roles of this polymorphism require a further investigation.