Noncardia Gastric Carcinoma Research Articles

Combined risk factors and risk of upper gastrointestinal cancer mortality in the Linxian general population.

We aimed to explore the association of combined risk factors with risk of death from upper gastrointestinal (UGI) cancer, including esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC) and gastric noncardia carcinoma (GNCC) in the Linxian Nutrition Intervention Trial (NIT) cohort. The NIT cohort included 29 584 healthy adults. A combined risk score (CRS) was calculated using a point system method based on 10 risk factors collected at baseline, including gender, smoking, alcohol drinking, body mass index, family history of UGI cancer, drinking tap water, tooth loss and consumption of fresh fruit, eggs and meat. Possible score ranged from 0 to 31, and higher score indicated as poorer health status. Subjects were divided into three groups by the CRS (<12 points, 12 to 20 points and >20 points). The group of CRS <12 points was considered as the reference. During the 30-year follow-up, we identified 4553 UGI cancer deaths. Compared to subjects with a CRS <12 points, the adjusted HRs for CRS of 12 to 20 points and >20 points were 1.69 (95% CI: 1.56-1.83) and 3.06 (95% CI: 2.82-3.33) for UGI cancer mortality, respectively (Ptrend < .001). Comparable associations were also observed for ESCC, GCC and GNCC mortality. Results remained similar across different age groups (Pinteraction > .05). All HRs observed in the second half follow-up period were stronger than that observed in the first half follow-up period. Our study indicated that higher CRS was associated with increased risk of UGI cancer mortality. Appropriate measures should be taken to reduce unhealthy lifestyles.

The Association Between Family History of Upper Gastrointestinal Cancer and the Risk of Death from Upper Gastrointestinal Cancer-based on Linxian Dysplasia Nutrition Intervention Trial (NIT) Cohort.

ObjectiveExplore the influence of family history of upper gastrointestinal (UGI) cancer on UGI cancer death, based on the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.MethodsFamily history of UGI cancer was defined as at least one first-degree relative (parent, child, or sibling) had a history of esophageal or gastric cancer. Cancer death was carried out by ICD-10 code. Family history information was collected at baseline and cancer deaths were assessed at each annual follow-up. The COX proportional risk model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). We compared the positive family history group with the negative to determine the risk of family history on UGI cancer death. The effect of category of relatives, number of relatives with UGI cancer, and diagnosis age of relatives on the UGI death risk were further analyzed. Interaction and stratification analyses were done to see the subgroup effects. Sensitivity analyses were also conducted by exclusion of individuals who were followed up less than three years. We considered controlling of covariates including: gender, age (continuity), community, education level, number of siblings (continuity), BMI (continuity), smoking, alcohol use, fresh fruit intake, fresh vegetable intake, hot beverage intake, edible oil intake, meat intake, and moldy staple food intake. All food intake variables were converted into categorical variables.ResultsFrom1985 to2015, we followed up total 3,318 individuals with 898 UGI cancer deaths (537 from ESCC, 77 from GNCC, and 284 from GCC). In a single factor analysis, family history of UGI cancer increased the risk of death of esophageal squamous cell carcinoma (ESCC) by 27% (HR=1.270, 95%CI1.072-1.504). No associations were observed in gastric cardia carcinoma (GCC) and gastric non-cardia carcinoma (GNCC). After adjusting for multi-factor, a family history of UGI cancer risk of death increased by 31.9% from ESCC (HR=1.319,95%CI:1.110-1.567). Subgroup analysis of different types of relatives with UGI cancers, UGI cancers in the mother (HR=1.457,95%CI:1.200-1.768), brother (HR=1.522,95%CI:1.117-2.073), and sister (HR=1.999,95%CI:1.419-2.817) were independent risk factors for ESCC death, while the father was not. In addition, 2 relatives with UGI cancer (HR=1.495, 95%, CI:1.110-2.013) and ≥3 relatives with UGI cancer (HR=2.836, 95%CI:1.842-4.367) significantly increased the risk of ESCC death, and the trend test was statistically significant (P<0.001). Relatives’ diagnostic age of 51-60 years (HR=1.322, 95%CI:1.046-1.672) and 41-50 years (HR=1.442, 95%CI:1.078-1.930) were the risk factors for ESCC death, with statistical significance in the trend test (P=0.010). No statistically significant result of the family history effect on the risk of death from GCC or GNCC was found. Sensitivity analysis of 80% of subjects, randomly selected, did not change the results.ConclusionA family history of UGI cancer may predict the risk of death from ESCC but not from GCC or GNCC. UGI cancer in the mother may predict the risk of death from ESCC, but not father, which indicates gender differences. Gender and smoking are the interaction items with family history in a similar extent. In the subgroup, the risk of ESCC death is more distinct by family history in younger, female, and better-lifestyle individuals, which indicates the unique role of genetic factors.

Family History and Risk of Upper Gastrointestinal Cancer in the Linxian General Population.

ObjectiveThe objective of this study was to investigate family history (FH) of upper gastrointestinal (UGI) cancer and risk of esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric non-cardia carcinoma (GNCC) in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. Methods: This prospective analysis was conducted using the Linxian NIT cohort data. Subjects with FH of UGI cancer was treated as an exposed group while the remainders were considered as a comparison group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between FH of UGI cancer and risk of UGI cancer incidence and mortality were estimated using Cox proportional hazards models.ResultsThere were 5,680 newly diagnosed UGI cancer cases during the follow-up period, with a total of 4,573 UGI cancer deaths occurred, including 2,603 ESCC, 1,410 GCC, and 560 GNCC deaths. A positive FH of UGI cancer was associated with a significantly increased risk of ESCC and GCC (Incidence: HRESCC = 1.45, 95%CI: 1.35–1.56; HRGCC = 1.27, 95%CI: 1.15–1.40; Mortality: HRESCC = 1.40, 95%CI: 1.30–1.52; HRGCC = 1.27, 95%CI: 1.14–1.42) after adjusting for age at baseline, gender, smoking status, alcohol drinking, education level, and frequency of fresh fruit and vegetable consumption. Subjects with FH in both parents had the highest risk of ESCC and GCC incidence (HRESCC = 1.65, 95%CI: 1.40–1.95; HRGCC = 1.42, 95%CI: 1.12–1.81) and deaths (HRESCC = 1.65, 95%CI: 1.38–1.97; HRGCC = 1.42, 95%CI: 1.09–1.85). Spouse diagnosed with UGI cancer did not increase the risk of any UGI cancers of the subjects. In subgroup analysis, FH of UGI cancer was shown to significantly increase the risk of GCC in non-drinkers (Incidence: HR = 1.31, 95%CI: 1.17–1.47; Mortality: HR = 1.33, 95%CI: 1.17–1.50). No associations were observed for risk of GNCC. Sensitivity analysis by excluding subjects who were followed up less than three years did not materially alter our results.ConclusionOur data point to the role of the FH of UGI cancer to the risk of ESCC and GCC incidence and mortality. The influence of family history on the risk of UGI cancer varies from different types of family members.

Oral leukoplakia and the long-term risk of upper gastrointestinal cancer deaths in the Linxian dysplasia population.

BackgroundTo investigate oral leukoplakia (OL) and risk of upper gastrointestinal (UGI) cancer deaths in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.MethodsA total of 3318 subjects with esophageal squamous dysplasia enrolled on 1 May 1985, and were followed up until 30 September 2015. Participants with OL at baseline were treated as an exposed group, while the remainder was selected as a control group. All subjects were followed monthly and reviewed quarterly by the Linxian Cancer Registry. Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).ResultsDuring the 30‐year follow‐up, a total of 902 UGI cancer deaths occurred, including 541 esophageal squamous cell carcinoma (ESCC) related, 284 gastric cardia carcinoma (GCC) related, and 77 gastric noncardia carcinoma (GNCC) related deaths. Relative to subjects without OL, the long‐term risk of ESCC mortality in participants with OL increased by 26.1% (HR = 1.26, 95% CI: 1.05–1.52). In the subgroup analyses, adverse effects of OL on ESCC mortality were observed especially in younger subjects (HR = 1.48, 95% CI: 1.11–1.97), females (HR = 1.44, 95% CI: 1.11–1.89), non‐smokers (HR = 1.44, 95% CI: 1.15–1.81), nondrinkers (HR = 1.28, 95% CI: 1.04–1.57), and individuals with a family history of cancer (HR = 1.37, 95% CI: 1.05–1.79). No associations were observed between OL and risk of GCC and GNCC mortality.ConclusionsOL may increase the long‐term risk of ESCC mortality, especially in younger subjects, females, nondrinkers, non‐smokers, and subjects with a family cancer history. Future studies are needed to explore the potentially etiological mechanism.

Fresh fruit consumption may decrease the long-term risk of esophageal cancer mortality: A 30-year follow-up study in the Linxian Dysplasia Nutrition Intervention trial (NIT).

BackgroundThe objective of this study was to explore the association between fresh fruit consumption and long‐term risk of upper gastrointestinal cancer (UGI) in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.MethodsA cohort of 3318 subjects with esophageal squamous dysplasia participated in the Linxian Dysplasia NIT in May 1985 and were followed up until 30 September 2015. Demographic characteristics, lifestyle, and history of diseases were collected at the baseline. The primary endpoint was death from esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric noncardia carcinoma (GNCC). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model.ResultsIn the 30‐year follow‐up, a total of 541 ESCC, 284 GCC, and 77 GNCC deaths occurred. Relative to those who never or rarely consumed fresh fruit, the risk of ESCC mortality in participants who consumed fresh fruit more than 12 times/year were significantly decreased by 37.3% (HR = 0.63, 95% CI: 0.49–0.81). In the subgroup analyses, significantly protective effects on ESCC mortality were observed especially in females (HR = 0.59, 95% CI: 0.40–0.89), non‐smokers (HR = 0.67, 95% CI: 0.48–0.94), and nondrinkers (HR = 0.69, 95% CI: 0.51–0.93).ConclusionsConsuming fresh fruit more than 12 times/year may reduce the long‐term risk of ESCC mortality in this dysplasia population, particularly in females, non‐smokers, and nondrinkers. Future studies are needed to confirm these findings.

Disadvantages for non-Hispanic whites in gastric carcinoma survival in Florida.

The prognosis for gastric carcinoma (GC) remains challenging with less than 35% of patients surviving 5years. GC survival varies greatly by anatomical site, cardia and non-cardia. However, these important differences have not been thoroughly studied in relation to the increasing diversity in US populations such as Florida. In this study we examined, for the first time, the effect of race-ethnicity on risk of death from GC controlling for potential risk factors separately for cardia and non-cardia GCs. Data on GCs diagnosed in Florida from 2005-2016 were obtained from the statewide cancer registry. Age-standardized GC-specific 5-year survival was computed by anatomical site and race-ethnicity. In addition, a competing risk analysis was performed to assess prognostic factors and to estimate subdistribution hazard ratios of death from GC. Whites had high proportions of cardia GC (43.9%) compared to all racial/ethnic minorities (10.9%, 19.6%, and 13.8% in Blacks, Hispanics, and Asians, respectively; p < .0001). Among 12,302 cases included, there were 7534 deaths from GC and 1179 from other causes. Age standardized GC-specific 5-year survival was significantly lower for Whites (28.0%) compared to Blacks (31.6%), Hispanics (37.6%), and Asians, (39.6%) and significantly lower for cardia GC (25.0%, 95% CI 23.4-26.6) compared to non-cardia GC (37.0%, 95% CI 35.5-38.4). Multivariable competing risk analysis in patients with non-cardia GC showed that Asians (sHR: 0.64, 95% CI 0.51-0.80), Hispanics (sHR 0.71, 95% CI 0.64-0.78), and Blacks (sHR 0.83, 95% CI 0.75-0.92) all had lower risks of death from GC compared to Whites. In patients with cardia GC, only Hispanics had statistically significant lower risk of death from GC than Whites (sHR 0.84, 95% CI 0.74-0.95, p = 0.005). The study of racial/ethnic survival disparities in patients with GC in Florida reveals Whites as the most disadvantaged group. Whites are more afflicted by cardia GC, which is associated with higher risk of death than non-cardia GC. However, even within non-cardia GC, Whites had higher risk of death than the other racial-ethnic groups. Commonly assessed survival determinants do not adequately explain these unusual disparities; thus, further investigation is warranted.

Body mass index and risk of upper gastrointestinal cancer: A 30-year follow-up of the Linxian dysplasia nutrition intervention trial cohort

BackgroundAlthough a number of previous studies have noted the association between body mass index (BMI) and upper gastrointestinal (UGI) cancer risk, little evidence exists in the Chinese esophageal squamous dysplasia population. This prospective study investigated the association between BMI and UGI cancer risk in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. MethodsA total of 3298 participants were included in the final analysis. Asian-specific BMI cut-offs were used to define BMI subgroups: underweight <18.5 kg/m2, normal ≥18.5 to <24 kg/m2 and overweight or obese ≥24 kg/m2. Hazard ratios (HRs) and 95 % confidence intervals (95 %CIs) were estimated using the Cox proportional hazard model. ResultsDuring over 30 years of follow-up we identified 654 incident esophageal squamous-cell carcinoma (ESCC) cases and 434 gastric cancer cases which included 88 gastric non-cardia carcinoma (GNCC) and 346 gastric cardia carcinoma (GCC) cases. Relative to normal weight, overweight or obesity were associated with a significantly reduced risk of ESCC (HR 0.69, 95 %CI 0.48–0.98) after multivariate adjustment, including age at baseline, gender, smoking, drinking, family history of cancer, education and consumption of fresh fruit. Subgroup analyses found that clear effects were evident in women and subjects with a family history of cancer. No association with gastric cancer was observed in any subjects or subgroups. ConclusionOverweight/obesity was associated with decreased risk of ESCC in this dysplasia population, particularly in women and persons who had a family history of cancer. Future studies are needed to confirm these findings.

Association between tooth loss and upper gastrointestinal cancer: A 30-year follow-up of the Linxian Dysplasia Nutrition Intervention Trial Cohort.

BackgroundThis prospective study investigated the association between tooth loss and upper gastrointestinal (UGI) cancer mortality in the Linxian Dysplasia Nutrition Intervention Trial Cohort.MethodsSubjects were categorized into three groups according to age at baseline. No missing teeth and less or greater than median tooth loss in each group was defined as none, moderate, and severe, respectively. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model.ResultsThrough 30 September 2015, 541 esophageal squamous cell carcinoma (ESCC), 284 gastric cardia carcinoma (GCC), and 77 gastric non‐cardia carcinoma (GNCC) deaths occurred. In the six‐year follow‐up, severe tooth loss was associated with an increased risk of GCC mortality (HR 1.55, 95% CI 1.06–2.18). In the 15‐year follow‐up, moderate tooth loss increased the ESCC mortality risk by 58% (HR 1.58, 95% CI 1.06–2.35), while severe loss increased the GCC mortality risk by 30% (HR 1.30, 95% CI 1.03–1.64). In the 30‐year follow‐up, moderate tooth loss increased the risk of ESCC mortality (HR 1.34, 95% CI 1.01–1.76). In subjects aged < 55 at baseline and men, moderate tooth loss had 53% and 52% higher risks of ESCC mortality (HR<55 years 1.53, 95% CI 1.06–2.05; HRmen 1.52, 95% CI 1.01–2.28). No significant association was observed for GNCC in any subjects or subgroups.ConclusionModerate tooth loss increased the risk of ESCC mortality, particularly in younger subjects and men. Severe tooth loss increased the risk of GCC mortality. Future studies are needed to confirm these findings.

Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.

Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high ALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH+ cells represented a core within the CD44+/CD166+ subpopulation that contained the highest frequency of tumorigenic CSCs in vivo The ALDH+ cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH- cells, a process that was partially reversed by verapamil treatment.Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586-97. ©2016 AACR.

Presence of Barrettʼs Esophagus Is Associated with Earlier Stage Gastric Cancer

Introduction: Adenocarcinoma of the esophagus, gastroesophageal junction (GEJ) and gastric cardia is increasing in incidence in the United States (US) while non-GEJ/cardia gastric carcinoma (GC) appears to be decreasing. Barrett's esophagus (BE) is the precursor lesion for esophageal and GEJ adenocarcinoma, but its association with non-cardia GC, if any, has not been well-characterized. Methods: We performed a retrospective analysis of patients with histologically confirmed non-cardia GC who also had endoscopic data available from 2008-2016 at a single NYC academic center. Age at diagnosis, race/ethnicity, smoking and alcohol status, presence of histologically confirmed BE, GC stage, GC location, and Helicobacter pylori status were recorded. Statistical analysis was performed in STATA. Results: 108 patients [67.6% men/32.4% women] met inclusion criteria. Mean age at diagnosis of GC was 70.1+/-11.0 years. 8.3% (n=9/108) had concomitant BE confirmed on histopathology (6 men/3 women). Compared to the overall cohort, there was no difference in age at GC diagnosis (66.7 +/- 3.5 years), or in race/ethnicity among patients with BE. These patients had earlier stages of GC (77.8% (n=7/9) stage 0 or 1; 22.2% (n=2/9) missing; 0% stage >2) at presentation compared to those without BE (40.4% (n=40/99) stage 0 or I, 41.4% (n=40/99) stage >2, and 17.2% (n=17/99) missing), Fischer's exact test p=0.02. H. pylori was only present in 7.4% (n=8/108) of patients overall and was not significantly associated with the presence or absence of BE (p=0.59). 44.4% (n=4/9) patients with BE were current/former smokers, while 55.6% (n=5/9) reported current/former alcohol use (compared to 42.6% and 26.9%, respectively in the overall cohort). In these 9 patients with concomitant BE, 4 had GC located in the body/fundus (44.4%), 4 in the incisura (44.4%), and 1 in antrum (11.1%). No BE had concomitant dysplasia or adenocarcinoma. Conclusion: In this multi-racial/ethnic cohort with histopathologically confirmed non-GEJ, non-cardia GC, we found an association between the presence of BE and earlier stage (0 or 1) gastric cancer. Further investigation into these findings and confirmation in a larger cohort is needed.

Interleukin‐1B and interleukin‐1 RN polymorphisms and gastric carcinoma risk: A meta‐analysis

We aimed to explore the role of interleukin (IL)-1B cluster gene polymorphisms at positions -511, -31, and +3954 and the receptor IL-1RN variable number tandem repeat polymorphisms in the susceptibility to gastric carcinoma through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. The desirable data were extracted and registered into databases. Studies that deviated from Hardy-Weinberg equilibrium were excluded. Eighteen studies were ultimately eligible for the meta-analysis of IL1B-511, 21 studies for IL1B-31, 10 studies for IL1B+3954, and 20 studies for IL1RN variable number tandem repeat genetic polymorphisms, respectively. Original groups were collapsed and re-grouping was adopted in line with the most probably appropriate genetic models. Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and biases across studies were estimated. The pooled odds ratios (95% confidence intervals, P-value) associated with IL-1B -511 T carriers versus CC genotypes and with RN *2 carriers versus L/L were 1.23 (1.04-1.45, P = 0.015) and 1.26 (1.06-1.51, P = 0.010), respectively, for overall gastric carcinoma; 1.31 (1.04-1.64, P = 0.020) and 1.47 (1.21-1.79, P = 0.000), respectively, for non-cardia gastric cancer; 1.55 (1.05-2.28, P = 0.026) and 1.66 (1.23-2.25, P = 0.001), respectively, for intestinal type gastric carcinoma; and 1.33 (1.04-1.71, P = 0.023) and 1.31 (1.07-1.61, P = 0.010), respectively, in Caucasians for overall gastric carcinoma. The pooled odds ratio (95% confidence interval, P-value) regarding IL-1B-31 CC plus TT versus CT was 0.73 (0.60-0.89, P = 0.002) for intestinal type gastric carcinoma. Genotyping methods and publication time could constitute the sources of heterogeneity across studies. Publication biases were not found. IL-1B -511 T allele and IL-1 RN *2 VNTR are significantly associated with an increased risk of developing gastric carcinoma and even more significantly with non-cardia gastric carcinoma or with intestinal-type gastric carcinoma. Both are significantly associated with an increased risk of developing gastric carcinoma among Caucasians, but not among Asians or Hispanics.

Changing incidence of gastric and oesophageal cancer subtypes in central Switzerland between 1982 and 2007

Several Western countries have reported a decrease in the incidence of noncardia gastric adenocarcinoma and a strong increase in the incidence of oesophageal and cardia adenocarcinoma. We examined incidence rates of gastric and oesophageal cancer by subsite and histology in Central Switzerland over the last 26 years. Data on biopsy-diagnosed gastric and oesophageal carcinoma incidence during 1982-2007 were obtained from the Cancer Registry of the Institute of Pathology, Lucerne, the Medical Centre for Central Switzerland. Age-adjusted (standardized to the European standard population), and sex-specific incidence rates were calculated. In total, 2,322 cancers were diagnosed: 1,240 noncardia gastric adenocarcinomas, 459 cardia gastric adenocarcinomas, 248 oesophageal adenocarcinomas, and 375 squamous cell carcinomas. From 1982 to 2007, the incidence rates of noncardia adenocarcinoma decreased substantially from 17.9 (per 100,000) to 6.0 in men and 10.3 to 5.5 in women. In men, the incidence of gastric cardia adenocarcinoma decreased from 7.5 to 4.3, the incidence of oesophageal adenocarcinoma increased from 3.3 to 4.8, and the incidence of oesophageal squamous cell carcinoma decreased from 6.6 to 4.1; the incidence rates of these cancers were low in women (1.1-2.4). In conclusion, the incidence of gastric noncardia carcinoma has decreased substantially over the past 26 years. In contrast to other Western countries, the incidence of gastric cardia adenocarcinoma did not increase in Central Switzerland. Whereas the rate of oesophageal adenocarcinoma increased, the rate of squamous cell carcinoma decreased. These results suggest substantial changes in environmental and life-style risk factors over the past 26 years.

Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a chinese population

Genetic factors play important roles in pathogenesis of human cancer. A recent genome-wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate stem cell antigen (PSCA), rs2294008C>T and rs2976392G>A, to risk of diffuse-type of gastric cancer in Japanese and Korean populations. We hypothesized that these two SNPs are also associated with risk of gastric cancer in Chinese population. We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13-1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01-1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to developing poorly differentiated and high stage NCGC at diagnosis. However, no such association was detected for CGC. In addition, we observed considerably lower allelic and genotype frequencies of these genetic variants in Chinese population compared with Japanese and Korean populations. These findings are in general consistent with previous GWAS and suggest that PSCA may play a role in the development of NCGC in Chinese population.

CD14-159C/T and TLR9-1237T/C polymorphisms are not associated with gastric cancer risk in Caucasian populations

Host genetic factors play an important role in modifying the risk of human disease, including cancers of the upper gastrointestinal tract, with increasing interest in Toll-like receptor (TLR) signaling and the impact of genetic polymorphisms in these systems. The CD14-159C/T and the TLR9-1237T/C promoter polymorphisms have previously been shown to be associated with various inflammatory conditions including Helicobacter pylori-induced gastritis in Caucasian populations. In this study, we assessed the association of these two functional single nucleotide polymorphisms with gastric cancer in two independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. No significant association was found between the CD14-159C/T and the TLR9-1237T/C promoter polymorphisms and increased risk of gastric cancer. Neither single nucleotide polymorphism has been assessed in a Caucasian gastric cancer case-control study before; although the CD14-159C/T polymorphism has been reported to show no apparent association with H. pylori-related gastric malignancy in a Taiwanese Chinese population. In conclusion, although our earlier preliminary studies suggested that the CD14-159C/T and the TLR9-1237T/C promoter polymorphisms increase the risk of precancerous outcomes, they do not seem to increase the risk of gastric cancer itself. This discrepancy merits further examination.

The Helicobacter pylori duodenal ulcer promoting gene, dupAin China

BackgroundThe prevalence of H. pylori is as high as 60–70% in Chinese population. Although duodenal ulcer and gastric cancer are both caused by H. pylori, they are at opposite ends of the spectrum and as such are considered mutually exclusive. Duodenal ulcer promoting (dupA) gene was reported to be associated with duodenal ulcer development. The aim of this study was to determine the prevalence of dupA gene of Helicobacter pylori in patients with various gastroduodenal diseases and to explore the association between the gene and other virulence factors.MethodsH. pylori were isolated from gastric biopsies of patients with chronic gastritis, duodenal ulcer (DU), gastric ulcer (GU), or non-cardia gastric carcinoma. The dupA, cagA, vacA, iceA and babA2 genotypes were determined by polymerase chain reaction. Histological features of gastric mucosal biopsy specimens were graded based on the scoring system proposed by the updated Sydney system. IL-1β polymorphism was investigated using restriction fragment length polymorphism.ResultsIsolates from 360 patients including 133 with chronic gastritis, 101 with DU, 47 with GU, and 79 with non-cardia gastric carcinoma were examined. The dupA gene was detected in 35.3% (127/360) and the prevalence DU patients was significantly greater than that in gastric cancer or GU patients (45.5% vs. 24.1% and 23.4%, P < 0.05). Patients infected with dupA-positive strains had higher scores for chronic inflammation compared to those with dupA-negative strains (2.36 vs. 2.24, p = 0.058). The presence of dupA was not associated with the cagA, vacA, iceA and babA 2 genotypes or with IL-1β polymorphisms.ConclusionIn China the prevalence of dupA gene was highest in DU and inversely related to GU and gastric cancer.

Alcohol dehydrogenase 3 and risk of esophageal and gastric adenocarcinomas

Alcohol increases esophageal squamous carcinoma risk but has been less consistently associated with esophageal adenocarcinoma. Alcohol dehydrogenase catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a carcinogen. The alcohol dehydrogenase gene has several polymorphisms which may lead to faster conversion of ethanol to acetaldehyde, which may increase cancer risk. We undertook a study to examine whether a common polymorphism in the alcohol dehydrogenase 3 gene was associated with a higher risk of esophageal adenocarcinoma using data and biological samples collected for the Esophageal and Gastric Cancer Study (n = 114 esophageal and gastric cardia adenocarcinoma, n = 60 non-cardia gastric carcinoma, n = 23 cases of esophageal squamous cell carcinoma and 160 controls). Individuals homozygous for ADH ( 3 ) (1-1) had a higher risk of each tumor type compared to individuals who had ADH ( 3 ) (2-2) or ADH ( 3 ) (1-2) genotype (OR = 1.7, 95% CI = 1.0-2.9 for esophageal and gastric cardia adenocarcinomas; OR = 1.7, 95% CI = 0.7-4.3 for esophageal squamous cell carcinoma; and OR = 2.8, 95% CI = 1.5-5.1 for non-cardia gastric cancer). The elevation in risk from homozygosity of the ADH ( 3 ) (1) allele was seen in drinkers and nondrinkers, although the risk estimate was only significant for drinkers, particularly of liquor. These data suggest ADH3 genotype may be associated with risk of esophageal and gastric cardia adenocarcinomas.

Use of Anti-Inflammatory Drugs and Lower Esophageal Sphincter–Relaxing Drugs and Risk of Esophageal and Gastric Cancers

The incidence of esophageal and gastric cardia adenocarcinoma has increased in Western countries in recent decades for largely unknown reasons. We investigated whether use of LES-relaxing drugs was related to an increased risk of esophageal and gastric cardia adenocarcinoma, and whether use of NSAIDs was related to a reduced risk of esophageal and gastric cancers. We examined these associations by using administrative databases in a case-control study in 2 integrated health care delivery systems. Cases were incident esophageal adenocarcinomas (n = 163) and squamous cell carcinomas (n = 114) and gastric cardia (n = 176) and non-cardia adenocarcinomas (n = 320), diagnosed between 1980-2002 in one health system and between 1993-2002 in the other. Matched controls (n = 3996) were selected. Complete prescription information was available for the study period. Prescription of corticosteroids was associated with a decreased risk of esophageal adenocarcinoma (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.4-0.9), esophageal squamous cell carcinoma (OR, 0.4; 95% CI, 0.2-0.6), and gastric non-cardia carcinoma (OR, 0.4, 95% CI, 0.3-0.6). Ever use of pharmacy-purchased aspirin was associated with 30%-60% decreased risks of the studied cancers. As a group, LES-relaxing drugs showed little evidence of association with increased risk of any esophageal or gastric cancer. Corticosteroid and aspirin use were associated with significantly decreased risks of esophageal and gastric cancer. LES-relaxing drugs as a group did not affect these risks, although we had limited power to assess individual drugs. The possibility that corticosteroids and aspirin might reduce esophageal cancer risk warrants further consideration.

Rugal hyperplastic gastritis increases the risk of gastric carcinoma, especially diffuse and p53-independent subtypes

Infection with Helicobacter pylori has been linked to chronic gastritis with atrophy or hyperrugosity. The development of noncardia gastric carcinoma, especially the intestinal type in Lauren's classification, has been associated with severe atrophic gastritis and p53 mutations. The objective of this study was to determine the association between hyperrugosity and gastric carcinogenesis, including p53 mutations. Barium meal roentgenograms were performed in 395 control participants and 132 gastric carcinoma patients. The fold width was measured at the greater curvature of the middle portion of the gastric body. Serum pepsinogens I and II were determined along with gastrin levels. Complete coding sequences and splice junctions for exons 5-8 of p53 gene were screened for mutations by polymerase chain reaction-based single-strand conformational polymorphism analysis. Rugal hyperplastic gastritis (gastric body fold width>or=5 mm) increased the risk of gastric carcinoma [odds ratio, 2.60; 95% confidence interval, 1.69-4.01] as compared with the control group, especially diffuse-type gastric carcinoma (odds ratio, 4.13; 95% confidence interval, 2.36-7.24). The p53 mutational rate was significantly lower in gastric carcinoma patients with rugal hyperplastic gastritis. In intestinal-type gastric carcinoma with hyperrugosity, the incidence of p53 gene mutations decreased, but no association was found in diffuse-type gastric carcinoma between p53 mutations and rugal hyperplastic gastritis. Rugal hyperplastic gastritis was associated with an elevated risk of gastric carcinoma, especially diffuse-type, and a lower frequency of p53 mutations.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

Interleukin‐8 gene polymorphism associated with susceptibility to non‐cardia gastric carcinoma with microsatellite instability

Gastric carcinoma (GC) with microsatellite instability (MSI) exhibits clinicopathological characteristics distinct from microsatellite-stable (MSS) GC. Both MSI and MSS carcinomas are mostly associated with chronic gastritis infected by Helicobacter pylori (Hp). The relationship between Hp-induced inflammation and the mutator pathway of MSI remains unclear. Recently, cytokine polymorphisms have been reported to affect the development of non-cardia GC. The objective of this study was to elucidate the relationship between cytokine polymorphisms and MSI phenotypes. In a case-control study including 482 controls and 181 patients with GC, interleukin (IL)-8 -251, IL-1B-511, IL-1RN, and tumor necrosis factor-A (TNFA) -857 polymorphisms were genotyped. The presence of MSI and mutations in exons 5 to 8 of the p53 gene were examined in GC cases. All clinicopathological data were collected from individual records. High and low frequency of MSI (MSI-H and MSI-L) and MSS were detected in 16 (8.8%), 14 (7.7%) and 151 (83.4%) GC cases, respectively. We found that IL-8 -251 T/T genotype was significantly associated with increased risk of MSI-H GC compared to MSI-L/MSS GC and controls. We found no association between other cytokine polymorphisms and MSI-H GC. The percentage of smokers and the frequency of p53 mutations were significantly lower in MSI-H than MSI-L/MSS GC. We found significant associations of MSI-H with synchronous or metachronous multiple occurrence, antral location and intestinal type. Our study shows that MSI-H GC is associated with IL-8-251 T/T (low expression genotype) and is inversely correlated with cigarette smoking.