Associations between a PTPN11 Polymorphism and Gastric Atrophy - Opposite in Uzbekistan to that in Japan

Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) of gastric epithelial cells interacts with cagA from Helicobacter pylori (H. pylori). Our previous studies found the AA genotype of a G/A single nucleotide polymorphism at intron 3 (rs2301756) of PTPN11 gene, which encodes SHP-2, to be associated with a lower risk of gastric atrophy. The present study aimed to examine the association with gastric atrophy among the subjects of a case-control study of peptic ulcer disease (PUD) conducted in the Uzbek Republic. Cases were 95 patients (61 males and 34 females) with PUD aged 16 to 85 years. Controls were 102 hospital volunteers (42 males and 60 females) including 42 patients with miscellaneous diseases, aged 15 to 75 years. Gastric atrophy was evaluated with serum pepsinogens (PG1<70ng/ml and PG1/PG2<3). Polymorphisms of PTPN11 at intron 3 (rs2301756) and intron10 (rs12229892) were genotyped with PCR with confronting two-pair primers (PCR-CTPP). Anti-cagA IgG antibody was detected in 93.7% of cases and 77.5% in controls. Gastric atrophy was observed in 24.2% of the PUD patients and 33.3% in the controls. The A allele at intron 3 was completely linked to the G allele at intron 10. The age, sex, and group (cases and controls) adjusted odds ratio of gastric atrophy was 0.18 (95% confidence interval, 0.04-0.86) for intron 3 GG genotype relative to AA genotype. Since the finding was opposite to that among Japanese, the H. pylori strains and/or lifestyle in Uzbekistan might modify the association.     

Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese

Helicobacter pylori (H. pylori) plays a crucial role in the development of gastric atrophy and cancer, and cagA-positive strains, which are universal in Japan, increase the risk of these outcomes substantially. The CagA protein is injected from attached H. pylori into gastric epithelial cells and undergoes Src-dependent tyrosine phosphorylation and activation of the eukaryotic phosphatase SHP-2. The CagA/SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. We investigated the association of a frequent single nucleotide polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene that encodes SHP-2 with gastric atrophy and gastric cancer in Japan. Gastric atrophy was assessed by measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy controls (126 males; mean age, 58.4) and 202 gastric cancer cases (134 males and 68 females; mean age, 66.7). All gastric cancer cases and 250 (55%) controls were H. pylori seropositive; 179 (89%) of the gastric cancer cases had gastric atrophy compared to 137 (55%) of the H. pylori seropositive controls (p < 0.001). Among HP seropositive controls compared to the common PTPN11 G/G genotype, the odds ratio of atrophy was nonsignificantly reduced with the G/A genotype (0.70; 95% CI = 0.39-1.25) and significantly reduced with the A/A genotype (0.09; 95% CI = 0.01-0.72). Lower risk for gastric atrophy had a gene-dose association with the A allele (p = 0.01, trend test). There was a clear deficiency of the A/A genotype in those with atrophy compared to those without (1 subject in the gastric atrophy group vs. 8 in the group without). Cancer cases differed from controls in frequencies of PTPN11 G/A genotype only because of a higher prevalence of atrophy among the cancer cases. The G/A SNP in the PTPN11 gene appears to be a risk factor for gastric atrophy in subjects infected with cagA-positive H. pylori. This may explain why only a proportion of CagA-positive individuals develop gastric atrophy and gastric cancer, even though infection with cagA strains is universal in Asian countries such as Japan. The functional consequences of the G/A polymorphism remain to be elucidated.     

Meta-analysis of the Association Between PTPN11 G/A Polymorphism at Intron 3 with Risk of Gastric Atrophy Among East Asians

Aim

Inconsistency of reported associations of the G/A polymorphism (rs2301756) in the PTPN11 gene and gastric atrophy prompted us to undertake a meta-analysis.

Materials and Methods

We searched PubMed for published literature up to July 2013. Individual data from studies with case-control design were evaluated for the PTPN11 G/A polymorphism in Helicobacter pylori (?) (seronegative) and (+) (seropositive) subjects (four studies each, totaling 3,597 cases and 4,865 controls).

Results

Associations of PTPN11 polymorphism with gastric atrophy in H. pylori (?) and (+) subjects are more readily interpreted in the homozygous and recessive models given that the dominant codominant effects skirted null associations. Thus, homozygous and recessive effects indicated reduced risk [odds ratio (OR) 0.92–0.96, p?=?0.51–0.74], which is significant among H. pylori (+) subjects (OR 0.66–0.68, p?=?0.04–0.05). Confined to the Japanese, reduced risk effects were unaltered in both groups, less protective among seronegative subjects (OR 0.85–0.86, p?=?0.71–0.73) than seropositive subjects with significance in the recessive model (OR 0.67, p?=?0.05). Sensitivity analysis demonstrated robustness of the seropositive findings, but probably not the seronegative results where homozygous and recessive pooled ORs were altered from protection to increased risk.

Conclusions

Evidence of overall and subgroup decreased risks, strong in seropositive subjects, demonstrates protective effects of the PTPN11 G/A polymorphism from gastric atrophy.     

Lifestyle factors associated with atrophic gastritis among <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-seropositive Japanese-Brazilians in SÃo Paulo

Background Studies of lifestyle factors related to gastric atrophy development in Helicobacter pylori-infected individuals are limited. The present cross-sectional study aimed to examine the associations between lifestyle factors and serum pepsinogens (PGs) among anti-H. pylori antibody-seropositive Japanese in Brazil, where gastric cancer mortality was reported to be as high as in Japanese in Japan, and seropositive individuals were still frequently detected.Methods The subjects were 291 seropositive individuals (129 males and 162 females; age, 30 to 69 years) out of 656 Japanese-Brazilian volunteers in SÃo Paulo city. Information on lifestyle factors was obtained using a self-administered questionnaire. Atrophic gastritis was defined as a PG1 serum level less than 70ng/ml and PG1/PG2 ratio less than 3.Results The prevalence of atrophic gastritis was 31.9% (95% confidence intervals, 26.6%–37.6%). The proportion of subjects with atrophic gastritis increased with age, but there were no significantly marked differences in the proportions of subjects with atrophic gastritis among the three generations studied (first generation [Issei], second generation [Nisei], and third generation [Sansei]) for any 10-year age group. The associations with smoking and alcohol drinking were not significant. Length of education was inversely associated with gastric atrophy, while infrequent rice intake was preventive; the odds ratio relative to everyday rice intake was 0.13 (95% confidence intervals, 0.39–0.46) on multivariate analysis.Conclusions The present study demonstrated that frequent rice intake was a risk factor for atrophic gastritis among the H. pylori-infected Japanese-Brazilians, suggesting that diet including rice plays a role in the step from H. pylori infection to gastric atrophy.     

Association between Helicobacter pylori seropositivity and NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism observed in outpatients and health checkup examinees

Background Significant associations of Helicobacter pylori (H. pylori) seropositivity have been found with several host polymorphisms. This study investigated the associations of functional polymorphisms of the NQO1, GSTM1, and GSTT1 genes of detoxification enzymes, with the seropositivity, as well as with pepsinogen levels, as markers of gastric atrophy.Methods The subjects were 241 noncancer outpatients who had participated in an H. pylori eradication program (HPE) at Aichi Cancer Center Hospital, and 465 health checkup examinees in Nagoya (HCE). The NQO1 C609T, GSTM1, and GSTT1 polymorphisms were determined by triplex polymerase chain reaction with confronting two-pair primers (PCR-CTPP).Results The sex- and age-group-adjusted odds ratio (OR) of NQO1 C/C for H. pylori seropositivity relative to T/T was highly significant; OR, 1.92; 95% confidence interval (95% CI), 1.22–3.03. The ORs of the GSTM1 present type and GSTT1 present type for H. pylori seropositivity were not significant; OR, 0.87; 95% CI, 0.64–1.20 and OR, 1.14; 95% CI, 0.83–1.57, respectively. The association of the NQO1 C/C genotype with H. pylori seropositivity was observed only for never-smokers; OR, 2.25; 95% CI, 1.33–3.79. The genotypes of the NQO1, GSTM1, and GSTT1 genes were not associated with the development of atrophic gastritis among the H. pylori-seropositive subjects.Conclusion This is the first study to report a significant association of the NQO1 C609T polymorphism with H. pylori seropositivity. The biological mechanism explaining the significant association with the seropositivity remains to be elucidated.     

Associations of TNF-A-1031TT and -857TT genotypes with Helicobacter pylori seropositivity and gastric atrophy among Japanese Brazilians

Background Our previous study in a Japanese population showed elevated Helicobacter pylori seropositivity in those with tumor necrosis factor (TNF) A -1031TT and -857TT genotypes. This study examined the associations of this seropositivity and serum pepsinogen (PG) levels with these genotypes in Japanese Brazilians. Methods The subjects were 963 individuals (399 males and 564 females), aged 33 to 69 years, from four regions (Sao Paulo, Curitiba, Mogi das Cruzes, and Mirandopolis) in Brazil. Gastric atrophy was evaluated with serum pepsinogens (PGI < 70 ng/dl and PGI/II < 3), and TNF T-1031C and C-857T were genotyped by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Results The frequency of TNF-A T-1031C was 68.4% TT, 28.4% TC, and 3.3% CC, and that of C-857T was 64.5% CC, 31.7% CT, and 3.8% TT, whose distributions were in Hardy-Weinberg equilibrium. No significant associations of the genotypes with H. pylori seropositivity or gastric atrophy were found. However, male participants with TNF-A -1031CC and -857CC showed the lowest seropositivity (43.8% out of 16), and males with TNF-A -1031TT and -857TT showed the highest (61.5% out of 13). Conclusion This study demonstrated that the associations between H. pylori seropositivity and TNF-A genotypes were not marked for Japanese Brazilians. The genotypes were not associated with gastric atrophy among the seropositive individuals.     

Association of <Emphasis Type="Italic">Helicobacter pylori </Emphasis>infection and diet on the risk of gastric cancer: a case–control study in Hawaii

Objective  The risk factors most strongly associated with gastric cancer are the gastric bacteria Helicobacter pylori and diet. Utilizing data from a case–control study among residents in Hawaii, we examined the association of diet, presence of H. pylori, and non-cardia gastric cancer risk. Methods  Serum taken at diagnosis for cases (n = 212) and at interview for controls (n = 336) was assayed for IgG antibodies to H. pylori group antigens and to a recombinant fragment of the cytotoxin-associated antigen A (CagA) protein, and subjects completed food frequency questionnaires. Risk measures were calculated using logistic regression. The likelihood ratio test was used to assess interactions. Results  Inverse associations were found between gastric cancer risk and increasing intake of several micronutrients and vegetables among all individuals. For H. pylori/CagA-positive subjects, significant trends were present for total, green, and yellow vegetables, while a significant trend was present only for yellow vegetables among H. pylori/CagA-negative individuals. For intestinal gastric cancer, there was a suggestion that intake of vegetables, especially cruciferous vegetables, had a stronger protective effect for the H. pylori/CagA-positive group. Conclusions  Diet may play a greater role in the etiology of non-cardia gastric cancer among individuals with evidence of H. pylori infection than among those without. G. N. Stemmermann is now deceased.     

Serum pepsinogen levels can quantify the risk of development of metachronous gastric cancer after endoscopic resection

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test‐positive, was significantly higher in patients with MGC (83 vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47–12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.     

Subjects with <Emphasis Type="Italic">TNF-A-857TT</Emphasis> and <Emphasis Type="Italic">-1031TT</Emphasis> genotypes showed the highest <Emphasis Type="Italic">Helicobacter pylori</Emphasis> seropositive rate compared with those with other genotypes

Background A possible association between Helicobacter pylori seropositivity and tumor necrosis factor (TNF) A G-308A has been reported in Korea. The present study examined the associations of H. pylori with functional polymorphisms, TNF-A G-308A, C-857T, and T-1031C, and TNF-B A252G in Japanese subjects.Methods The total of 1374 study subjects included 241 outpatients who participated in an H. pylori eradication program (HPE), 679 first-visit outpatients (FVO) at a regional cancer hospital, and 454 local residents who received a health checkup examination (HCE).Results The frequency of the TNF-A -308A allele was only 1.3% of 480 chromosomes in the HPE group, so the FVO and HCE groups were not genotyped for that polymorphism. The genotype frequency of TNF-A C-857T was 69.2% CC, 27.7% CT, and 3.1% TT; that of TNF-A T-1031C was 69.4% TT, 28.1% TC, and 2.5% CC; and that of TNF-B A252G was 36.8% AA, 48.2% AG, and 15.0% GG. TNF-A -857T was tightly linked to TNF-A -1031T and TNF-B 252A. No significant associations between H. pylori seropositivity and polymorphisms of TNF-A C-857T and TNF-B A252G were observed. However, a reduced odds ratio adjusted for sex, age, and recruitment source was observed for TNF-A -1031CC (0.43; 95% confidence interval, 0.20–0.91) relative to TNF-A -1031TT. Subjects with TNF-A -857CC and -1031CC showed the lowest seropositivity (38.2% of 34 participants), while those with TNF-A -857TT and -1031TT showed the highest (66.7% of 42 participants).Conclusions This study suggests that the possibly high expression genotype of TNF-A may increase susceptibility to persistent H. pylori infection.     

SNP interactions of Helicobacter pylori-related host genes PGC,PTPN11, IL1B,and TLR4 in susceptibility to gastric carcinogenesis

A series of host genes that respond to Helicobacter pylori (H. pylori) infection are involved in the process of gastric carcinogenesis. This study sought to examine interactions among polymorphisms of H. pylori-related genes PGC, PTPN11, TLR4, and IL1B and assess whether their interaction effects were modified by H. pylori infection. Thirteen polymorphisms of the aforementioned genes were genotyped by the Sequenom MassARRAY platform in 714 gastric cancer patients, 907 atrophic gastritis cases and 1276 healthy control subjects. When we considered the host genetic effects alone, gene–gene interactions consistently decreased the risks of gastric cancer and/or atrophic gastritis, including three two-way interactions: PGC rs6912200-PTPN11 rs12229892, PGC rs4711690-IL1B rs1143623 and PTPN11 rs12229892-IL1B rs1143623 and a three-way interaction: PGC rs4711690-PGC rs6912200-PTPN11 rs12229892. When the effect modification of H. pylori infection was evaluated, the cumulative effects of the aforementioned three-way interaction on atrophic gastritis susceptibility switched from being beneficial to being risky by the status of H. pylori infection. These data showed that SNP interactions among H. pylori-related genes PGC, PTPN11, and IL1B, are associated with susceptibility to gastric carcinogenesis. Moreover, we provided important hints of an effect modification by H. pylori infection on the cumulative effect of PGC and PTPN11 polymorphisms. Functional experiments and further independent large-scale studies especially in other ethnic populations are still needed to confirm our results.     

Inflammatory cytokine gene polymorphisms in gastric cancer cases' and controls' family members from Chinese areas at high cancer prevalence

The purpose of this study was to test the associations about Helicobacter pylori infection and polymorphisms of IL-1B-31/-511 and IL-1RN VNTR polymorphism with gastric cancer in cases’ and controls’ family members from the areas of high cancer prevalence in China. IL-1B-511T and IL-1RN*2 were associated with risks of gastric cancer. The association strength reduced with the relative degree decreasing. Such association was not found in the polymorphisms of IL-1B-31. But the haplotype analysis of IL-1B-511 and IL-1B-31 genotype could enhance the risks of gastric cancer. The positive H. pylori status could increase the risks of IL-1B to gastric cancer.     

Severe atrophic gastritis with Helicobacter pylori infection and gastric cancer

Background. We conducted a case-control study to evaluate whether patients with severe gastric atrophy (indicated by serum pepsinogen concentration) have a high risk of gastric cancer. Methods. At the time of diagnosis of gastric cancer, sera from 301 patients (cases) and 602 sex- and age-matched cancer-free individuals (controls) were tested for the presence of anti-Helicobacter pylori IgG antibody (HM-CAP enzyme-linked immunoassay [ELISA] kit; Kyowa Medix, Tokyo, Japan) and serum pepsinogen (PG) levels (PG I and II Riabead Kits; Dainabot, Tokyo, Japan). We defined positivity for pepsinogen a pepsinogen I concentration of less than 70 ng/mL and a PG I/II ratio of less than 3.0. We categorized the subjects according to serum pepsinogen levels and anti-Helicobacter pylori IgG antibody, creating four categories. Results. Of the 301 cancer cases, 177 had positive serum pepsinogen levels, and 172 were positive for anti-Helicobacter pylori IgG antibody. The category in which subjects had positive serum pepsinogen levels and were negative for anti-Helicobacter pylori IgG antibody had the highest proportion (76.9%) of individuals with gastric cancer and the highest odds ratio (4.20) of the four categories. The odds ratios were 2.55 (95% confidence interval; 1.92–3.88) for positive serum pepsinogen levels and 0.93 (95% confidence interval; 0.63–1.27) for positive anti-Helicobacter pylori IgG antibody. Conclusion. These results suggest that patients with positive serum pepsinogen levels who are negative for IgG antibody to Helicobacter pylori, constitute a high-risk group for gastric cancer. Helicobacter pylori infection is associated with the development of gastric cancer by providing a suitable environment i.e., severe gastric atrophy, for carcinogenesis of the gastric mucosa. Received for publication on Mar. 20, 1998; accepted on Aug. 20, 1998     

Association of <Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection and environmental factors in non-cardia gastric cancer in Japan

Background Although Helicobacter pylori infection is a major risk factor for gastric cancer, it does not explain the full picture of stomach carcinogenesis. There have been few epidemiological studies, however, which examined both H. pylori and environmental factors simultaneously. The aims of this study were to estimate the association of environmental factors (smoking and dietary factors) with gastric cancer in consideration of H. pylori infection, and to investigate the effects of the interaction between environmental factors and H. pylori infection.Methods A multicenter, hospital-based, case-control study of gastric cancer was conducted at four hospitals in Nagano prefecture, Japan, between October 1998 and March 2002. For 153 newly diagnosed gastric cancer cases, two controls matched by age (within 3 years), sex, and residence area were randomly selected from the participants of a health check-up program during the same period in the same hospitals. We conducted a questionnaire survey and obtained blood samples. Consequently, 122 non-cardia gastric cancer cases and 235 controls were available for this analysis.Results Results. H. pylori infection was strongly associated with non-cardia gastric cancer after adjustment for possible confounding factors (odds ratio [OR], 8.2; 95% confidence interval [CI], 3.7–18.2). Cigarette smoking (OR, 2.8; 95% CI, 1.2–6.5) and frequent intake of miso (fermented soy bean) soup (OR, 2.1; 95% CI, 0.9–5.1) and rice (OR, 2.5; 95% CI, 1.0–6.1) were determined to be risk factors even after adjusting for possible confounding factors, including H. pylori infection. However, no statistically significant interaction between environmental factors and H. pylori infection was detected.Conclusion This finding suggests that although H. pylori infection is clearly an important risk factor for gastric cancer, smoking cessation and dietary modification may be practical strategies for the prevention of non-cardia gastric cancer among both H. pylori-positive and -negative subjects in Japan.     

Genetic polymorphism in chemokine CCL22 and susceptibility to Helicobacter pylori infection‐related gastric carcinoma

BACKGROUND:

Gastric carcinoma is widely considered to be related to Helicobacter pylori infection, and the chemokine (C‐C motif) ligand 22 (CCL22) plays an important role in suppressing immune responses against H. pylori and tumor cells. In this study, the authors examined the association between single nucleotide polymorphisms (SNPs) in the CCL22 gene and the risk of gastric carcinoma.

METHODS:

Information on SNPs in the CCL22 coding region was obtained from the HapMap Project database. Genotypes were determined in a case‐control cohort that consisted of 1001 patients with gastric carcinoma and 1066 controls, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed by using a logistic regression model. Serum H. pylori antibody levels were measured by using an enzyme‐linked immunosorbent assay.

RESULTS:

The 16C→A SNP (reference SNP no. 4359426) in exon 1 of the CCL22 gene, which causes a 2 aspartate (2Asp) to 2 alanine (2Ala) substitution in the CCL22 protein, was associated with a significantly increased risk of gastric carcinoma. Individuals who were homozygous for the Ala/Ala genotype had an OR of 2.27 (95% CI, 1.28‐4.02) compared with individuals who had the Asp/Asp genotype. Stratification analysis indicated that the association was more pronounced among men (OR, 2.64; 95% CI, 1.29‐5.41) and among younger individuals (OR, 2.85; 95% CI, 1.36‐5.96) compared with women and older individuals. Moreover, a multiplicative joint effect between the CCL22 SNP and H. pylori infection that intensified the risk was observed (OR for the presence of both Ala/Ala genotype and H. pylori infection, 18.37; 95% CI, 2.30‐146.67).

CONCLUSIONS:

The results from this study suggested that the CCL22 polymorphism is associated with an increase risk of developing H. pylori infection‐related gastric carcinoma. Cancer 2009. © 2009 American Cancer Society.     

No association between AICDA 7888 C/T polymorphism, Helicobacter pylori seropositivity, and the risk of atrophic gastritis and gastric cancer in Japanese

Background  

The aberrant expression of activation-induced cytidine deaminase (AICDA) was reportedly induced in gastric epithelial cells infected with cytotoxin-associated gene A (cagA)-positive Helicobacter pylori, resulting in the accumulation of alterations in the TP53 tumor suppressor gene in gastric cells. We investigated the association of the AICDA 7888 C/T polymorphism with H. pylori infection and the risk of gastric cancer and atrophic gastritis in Japanese subjects.     

Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori‐associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori‐associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori‐negative/CAG‐negative), cancer incidence rate was low, at 16/100,000 person‐years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG‐free subjects (H. pylori‐positive/CAG‐negative) [hazard ratio (HR) = 8.9, 95% confidence interval (CI) = 2.7–54.7] to subjects with CAG (H. pylori‐positive/CAG‐positive) (HR = 17.7, 95% CI = 5.4–108.6) and finally to subjects with metaplastic gastritis (H. pylori‐negative/CAG‐positive) (HR = 69.7, 95% CI = 13.6–502.9). In H. pylori‐infected CAG‐free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation‐based high PG II level or potent immune response‐based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse‐type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person‐years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori‐infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis‐atrophy‐metaplasia‐cancer sequence and partly from active inflammation‐based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori‐infected subjects.     

No associations of Toll-like receptor 2 (TLR2) -196 to -174del polymorphism with the risk of Helicobacter pylori seropositivity, gastric atrophy, and gastric cancer in Japanese

Background  

Recently, the association between gastric cancer risk and a functional polymorphism of Toll-like receptor 2 (TLR2), -196 to -174del, was reported for a Japanese population. This study aimed to confirm the associations of the polymorphism with the risk of gastric cancer, as well as Helicobacter pylori seropositivity and the risk of gastric atrophy in Japanese.     

PRKCH gene polymorphism is associated with the risk of severe gastric atrophy

Background  

Individuals infected with Helicobacter pylori do not necessarily develop gastric atrophy (GA) and gastric cancer (GC). Several factors, including genetic polymorphism, can regulate the development of GA and GC. A G/A single nucleotide polymorphism (rs3783799) of the PRKCH gene, which encodes the η isozyme of protein kinase C (PKCη), has been reported to be a tag single nucleotide polymorphism (SNP) of the PRKCH gene linked to a functional 1425G/A SNP in exon 9 (rs2230500). To elucidate its applicability in the development of GA and GC, this study aimed to investigate the associations of the PRKCH polymorphism with the risks of GA and GC.     

IGHMBP2 Thr671Ala polymorphism might be a modifier for the effects of cigarette smoking and PAH–DNA adducts to breast cancer risk

Summary Laboratory and bioinformatics studies have suggested that immunoglobulin μ-binding protein 2 (IGHMBP2) is involved in DNA repair, replication and recombination. Using 1067 cases and 1110 controls from a population-based case-control study, we sought to clarify the potential role of the IGHMBP2 Thr671Ala polymorphism (A to G substitution) alone and as a modifier of the effects for cigarette smoking and PAH–DNA adducts on breast cancer risk. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Overall, there was no significant association between the IGHMBP2 variant-G allele and breast cancer risk (OR = 1.1, 95% CI = 0.9–1.3). Increased risk was found among women who had detectable PAH–DNA adducts and carried at least one variant-G allele (OR = 1.4, 95% CI = 1.0–1.8, p for trend = 0.01) compared to women carrying the wild-type AA genotype and with non-detectable adducts. Smokers carrying the IGHMBP2 variant-G allele had no significant increased breast cancer risk compared with non-smoking women with the AA genotype. Heavy smokers (>31 pack years) had a statistically significant association with breast cancer risk (OR=2.0, 95% CI=1.2–3.3) relative to nonsmokers with the AA genotype though the magnitude of association was not different than heavy smokers (> 31 pack years) with the AA genotype (OR=1.6, 95% CI=0.9–2.6). Overall our study observes only modestly higher effect estimates for PAH-DNA adduct exposure and cigarette smoking among those with the high-risk genotype, but these differences are not statistically significant. Additional studies focused on the biological function of the variant-G allele and interactions with other genetic polymorphisms are necessary to confirm our findings.     

Significance of SHP-1 and SHP-2 Expression in Human Papillomavirus Infected <Emphasis Type="Italic">Condyloma acuminatum</Emphasis> and Cervical Cancer

Human papillomaviruses (HPVs) are a group of DNA viruses that infect the skin and mucous membranes. Type HPV6/11 is closely related to Condyloma acuminatum, while HPV16/18 is the principal cause of cervical cancer. In this study, we examined the expression of protein tyrosine phosphatases SHP-1 and SHP-2 in Condyloma acuminatum, cervical cancer and the relationship between SHP-1/SHP2 expression and HPV infection. Forty Condyloma acuminatum cases, 20 cervical cancer cases and 20 normal human foreskins were examined for HPV infection by in situ hybridization and the expression of SHP-1 and SHP-2 were examined by immunohistochemistry. Results demonstrated that positive expression rates of HPV6/11, HPV16/18, and HPV31/33 were 98%, 10%, and 7.5% in Condyloma acuminatum, 10%, 85%, and 25% in cervical cancer. Only one normal foreskin demonstrated positive staining for HPV16/18. Positive expression rates of SHP-1 and SHP-2 were 80% and 85% in Condyloma acuminatum, 85% and 90% in cervical cancer. The SHP-1 and SHP-2 expressions were mainly distributed in the prickle layer of Condyloma acuminatum and were diffusely distributed in cervical cancer cells. Only 35% and 30% of foreskins demonstrated weak staining in the basal layer cells. There were statistically significant correlations among the infection of HPV and the expression of SHP-1 and SHP-2 in both Condyloma acuminatum and cervical cancer (P < 0.05). SHP-1 expression has a positive correlation with SHP-2 expression. Our results demonstrate putative roles of SHP-1 and SHP-2 in the progression of both Condyloma acuminatum and cervical cancer after HPV infection.