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1.  Serum pepsinogens and risk of esophageal squamous dysplasia 
Pepsinogens are a class of endopeptidases that are secreted by the gastric epithelium and released into the circulation. Low serum pepsinogen I (PGI) and low serum pepsinogen I / pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy, and have recently been shown to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). We conducted the current study to test whether these markers are also associated with esophageal squamous dysplasia (ESD), the precursor lesion of ESCC.
We measured serum PGI and PGII, using enzyme-linked immunosorbent (ELISA) assays, in 125 case subjects (patients with moderate or severe ESD) and 250 sex-matched control subjects (no ESD) selected from an endoscopic screening study in Linxian, China. We used conditional logistic regression models adjusted for age, smoking, and place of residence to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).
Serum PGI showed no statistically significant association with ESD, whether analyzed as a dichotomous, ordinal (quartiles), or continuous variable. Lower serum PGI/II ratio, however, showed a dose-response association with increased risk of ESD, with an adjusted OR (95% CI) of 2.12 (1.08 − 4.18), comparing the lowest versus the highest quartile. The association between lower serum PGI/II ratio and log OR of ESD was nearly linear, and the p-value for the continuous association was 0.03.
Lower serum PGI/II ratio was linearly associated with higher risk of ESD. This result is consistent with recent findings that gastric atrophy may increase the risk of ESCC.
doi:10.1002/ijc.23918
PMCID: PMC2605159  PMID: 18844222
Esophageal cancer; Squamous dysplasia; Pepsinogen; China
2.  Serum thyroglobulin, a biomarker for iodine deficiency, is not associated with increased risk of upper gastrointestinal cancers in a large Chinese cohort 
Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. This study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA, and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from approximately 200 subjects of each case type and 400 non-cases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex- and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history, and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted Hazard Ratios of 0.88 (95% confidence interval 0.50–1.52), 1.14 (0.63–2.05), and 0.78 (0.47–1.31) for GNCA, GCA, and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers.
doi:10.1002/ijc.25789
PMCID: PMC3075342  PMID: 21105043
iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China
3.  Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis 
PLoS ONE  2013;8(9):e74440.
Background
A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting.
Methods
In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared.
Results
Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)].
Conclusion
Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.
doi:10.1371/journal.pone.0074440
PMCID: PMC3787044  PMID: 24098650
4.  Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers 
British Journal of Cancer  2007;97(1):123-128.
We prospectively examined the relation between pretrial serum vitamin D status and risk of oesophageal and gastric cancers among subjects who developed cancer over 5.25 years of follow-up, including 545 oesophageal squamous cell carcinomas (ESCC), 353 gastric cardia adenocarcinomas, 81 gastric noncardia adenocarcinomas, and an age- and sex-stratified random sample of 1105 subjects. The distribution of serum 25(OH)D was calculated using the known sampling weights. For the cohort as a whole, the 25th, 50th, and 75th percentile concentrations of 25(OH)-vitamin D were 19.6, 31.9, and 48.7 nmol l−1, respectively, and we found that higher serum 25(OH)D concentrations were associated with monotonically increasing risk of ESCC in men, but not in women. Comparing men in the fourth quartile of serum 25(OH)D concentrations to those in the first, we found a hazard ratio (HR) (95% confidence interval (CI)) of 1.77 (1.16–2.70), P trend=0.0033. The same comparison in women had a HR (95% CI) of 1.06 (0.71–1.59), P trend=0.70. We found no associations for gastric cardia or noncardia adenocarcinoma. Among subjects with low vitamin D status, higher serum 25(OH)D concentrations were associated with significantly increased risk of ESCC in men, but not in women. Further refinements of the analysis did not suggest any factors, which could explain this unexpected result.
doi:10.1038/sj.bjc.6603834
PMCID: PMC2359654  PMID: 17551495
vitamin D; oesophageal cancer; gastric cancer; cohort study; China
5.  Helicobacter pylori infection and markers of gastric cancer risk in Alaska Native persons: A retrospective case-control study 
The high prevalence of Helicobacter pylori infection in Alaska Native people is believed to be a major contributor to the increased incidence of gastric cancer and mortality in this population. Due to several factors, however, general screening of this population for H pylori infection is highly impractical. Identifying associations between specific serological markers and gastric cancer, therefore, has been an emerging area of investigation. Prompted by the lack of data from this population, this retrospective study examined potential serological cancer markers from samples obtained years before cancer diagnoses.
BACKGROUND:
Alaska Native persons experience gastric cancer incidence and mortality rates that are three to four times higher than in the general United States population.
OBJECTIVE:
To evaluate pepsinogen I, pepsinogen I/II ratio, anti-Helicobacter pylori and cytotoxin-associated gene A (CagA) antibody levels, and blood group for their associations with gastric cancer development in Alaska Native people.
METHODS:
The present analysis was a retrospective case-control study that matched gastric cancers reported to the Alaska Native Tumor Registry from 1969 to 2008 to three controls on known demographic risk factors for H pylori infection, using sera from the Alaska Area Specimen Bank. Conditional logistic regression evaluated associations between serum markers and gastric cancer.
RESULTS:
A total of 122 gastric cancer cases were included, with sera predating cancer diagnosis (mean = 13 years) and 346 matched controls. One hundred twelve cases (91.8%) and 285 controls (82.4%) had evidence of previous or ongoing H pylori infection as measured by anti-H pylori antibody levels. Gastric cancer cases had a 2.63-fold increased odds of having positive anti-H pylori antibodies compared with their matched controls (P=0.01). In a multivariate model, non-cardia gastric cancer (n=94) was associated with anti-H pylori antibodies (adjusted OR 3.92; P=0.004) and low pepsinogen I level (adjusted OR 6.04; P=0.04). No association between gastric cancer and blood group, anti-CagA antibodies or pepsinogen I/II ratio was found.
CONCLUSION:
Alaska Native people with gastric cancer had increased odds of previous H pylori infection. Low pepsinogen I level may function as a precancer marker for noncardia cancer.
PMCID: PMC4072235  PMID: 24945184
Alaska Native; cagA+; Gastric cancer; Helicobacter pylori; Pepsinogen I
6.  Vitamin E intake and Risk of Esophageal and Gastric Cancers in the NIH-AARP Diet and Health Study 
We investigated the association of dietary α-tocopherol, γ-tocopherol, and supplemental vitamin E intake with the risk of esophageal squamous cell carcinoma (ESCC; n = 158), esophageal adenocarcinoma (EAC; n = 382), gastric cardia adenocarcinoma (GCA; n = 320), and gastric noncardia adenocarcinoma (GNCA; n = 327) in the NIH-AARP Diet and Health Study, a cohort of approximately 500,000 people. Data on dietary and supplemental vitamin E intake were collected using a validated questionnaire at baseline and were analyzed using Cox regression models. Intakes were analyzed as continuous variables and as quartiles.
For dietary α-tocopherol, we found some evidence of association with decreased ESCC and increased EAC risk in the continuous analyses, with adjusted hazard ratios (HR) and 95% confidence intervals (CI) of 0.90 (0.81 – 0.99) and 1.05 (1.00 – 1.11), respectively, per 1.17 mg (half the interquartile range) increased intake. However, in quartile analyses, the p-value for trend was non-significant for both of these cancers. There was no association between dietary α-tocopherol and GCA or GNCA. We observed no statistically significant associations with γ-tocopherol. For supplemental vitamin E, the results were mainly null, except for a significantly lower risk of GNCA with higher doses of supplemental vitamin E. An increase of 71 mg/day (half the interquartile range) in supplemental vitamin E had an HR (95% CI) of 0.92 (0.85–1.00) and the p-value for trend in the quartile analyses was 0.015.
doi:10.1002/ijc.24342
PMCID: PMC2686122  PMID: 19326432
7.  Association between upper digestive tract microbiota and cancer predisposing states in the esophagus and stomach 
Background
The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II) (predictor of gastric cancer risk), and esophageal squamous dysplasia (ESD) (the precursor lesion of esophageal squamous cell carcinoma (ESCC)) in a cross-sectional design.
Methods
The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by enzyme-linked immunosorbent assays. ESD was determined by chromoendoscopy with biopsy.
Results
Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio (P=0.034) and the presence of ESD (P=0.018). We conducted principal component (PC) analysis on a β-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3 and PGI/II (P=0.004, 0.009 respectively), and between PC1 and ESD (P=0.003).
Conclusions
lower microbial richness in upper digestive tract was independently associated with both cancer predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II).
doi:10.1158/1055-9965.EPI-13-0855
PMCID: PMC4011942  PMID: 24700175
microbiota; gastric cancer; esophageal squamous cell carcinoma; esophageal squamous dysplasia; serum pepsinogen I/pepsinogen II ratio
8.  Accuracy of pepsinogens for early diagnosis of atrophic gastritis and gastric cancer in Iranian population 
Background: Currently, non-invasive methods for screening atrophic gastritis and gastric cancer are lacking. The purpose of this study was to evaluate the value of serological parameters including serum pepsinogen I (PGI), pepsinogen II (PGII) and pepsinogen I: II ratio for the screening atrophic gastritis and gastric cancer.
Methods: The study population consisted of 132 dyspeptic patients who had undergone upper endoscopy with biopsy. Blood samples for ELISA assays of serum PGI, PGII and IgG antibodies against Helicobacter pylori were drawn. Comparison between the two groups was done by Student’s t- test, and Mann Whitney test. Cut-off points were calculated using receiver operating curves (ROC).
Results: Mean (±SD) age of the study population was 51.4 (±15.5) years. Values of PGI and PG ratio decreased significantly in the atrophic gastritis as compared with the control group (p<0.05). Values of PG and PG ratio didn’t show any significant difference between the gastric cancer and control group (p>0.05). For patients with atrophic gastritis, the area under the ROC for PGI was 0.639 (95% CI:0.538-0.741, p=0.008) in which the best cut-off value was 40μg/L (sensitivity 90%, specificity 67%, accuracy 69%, negative predictive value 92%, YI : 0.429). The area under the ROC for PG ratio was 0.711 (95% CI: 0.617–0.806, p=0.0001) and the best cut-off value was 8 (sensitivity 71%, specificity 71%, accuracy 71%, negative predictive value 86%,YI : 0.431).
Conclusion: It seems that PGI, PGI: PGII ratio is potential biomarkers for screening atrophic gastritis with high sensitivity, specificity, accuracy and negative predictive value. Serology could be used as a screening method for the detection of precancerous states due to its convenience, relative low cost and safety.
PMCID: PMC4322333  PMID: 25695008
Pepsinogens; Atrophic gastritis; Gastric cancer; Biomarkers
9.  Pepsinogen I and II expressions in situ and their correlations with serum pesignogen levels in gastric cancer and its precancerous disease 
Background
Serum pepsinogen (PG) I/II ratio has been widely used as “serological biopsy” for the screening of gastric cancer (GC) and atrophic gastritis (GA). However, study concerning in situ expression of PGs is currently insufficient, particularly for their relationship with serum PGs levels. This study was designed to investigate in situ expression of PGI and PGII in subjects with normal mucosa (NOR), superficial gastritis (GS), GA and GC, and to evaluate the correlations between PGs expressions in situ and in serum.
Methods
185 subjects were enrolled for the study, including 30 NOR, 70 GS, 54 GA and 31 GC. PGI and PGII expressions in situ and in serum were detected by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. H. pylori immunoglobulin (Ig) G was also determined by ELISA.
Results
In situ expressions of PGI, PGII and PGI/II ratio consistently decreased in sequence of NOR/GS- > GA- > GC. The expressions of PGI, PGII and PGI/II ratio in situ were statistically higher in youngers than in olders (P < 0.05). In the NOR subjects, PGI staining was statistically higher in males than that in females (p = 0.02). For the correlations between in situ and serum expressions of PGI, PGII and PGI/II ratio, a borderline correlation in the total study sample (r = 0.131, P = 0.076) and a statistical correlation in GA cases (r = 0.307, P = 0.027) were observed for the PGI/II ratio. The PGI expression correlated well with that of PGII in situ and in serum.
Conclusions
The in situ levels of PGI, PGII and PGI/II ratio sharply decreased in the GA and GC cases. The youngers exhibited higher levels of PGI, PGII and PGI/II ratios than the olders. The in situ PGI/II ratio rather than PGI and PGII alone showed certain correlation with that in serum, and the PGI expression correlated well with PGII expression. Further studies with large-scale samples are still required to validate our findings.
doi:10.1186/1472-6890-13-22
PMCID: PMC3846408  PMID: 24004680
Pepsinogen; Gastric disease; Correlation
10.  Index-Based Dietary Patterns and Risk of Esophageal and Gastric Cancer in a Large Cohort Study 
Background & Aims
Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers.
Methods
We analyzed data from 494,968 participants in the National Institutes of Health (NIH)-AARP Diet and Health study, in which AARP members (51–70 y old) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index.
Results
During the follow-up period (1995–2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest: hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.31–0.86; Ptrend=.001) and EAC (HR, 0.75; 95% CI, 0.57–0.98; Ptrend=.01). We observed an inverse association between ESCC, but not EAC, and higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not significantly associated with gastric cardia or noncardia adenocarcinomas.
Conclusions
Using data collected from 1995 through 2006 from the NIH-AARP Diet and Health Study, HEI-2005 and aMED scores were inversely associated with risk for esophageal cancers—particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers.
doi:10.1016/j.cgh.2013.03.023
PMCID: PMC3758458  PMID: 23591281
food habits; esophageal neoplasms; stomach neoplasms
11.  Prospective study of self-reported diabetes and risk of upper gastrointestinal cancers 
Background
While gastric noncardia adenocarcinoma (GNCA) incidence rates in the US have decreased, the rates of gastric cardia adenocarcinoma (GCA) and esophageal adenocarcinoma (EADC) have increased. Obesity increases the risks of GCA and EADC, and the associations may be partially mediated by insulin resistance. A few case-control studies have shown an association between diabetes and an increased risk of EADC.
Methods
We prospectively examined the association between diabetes and upper gastrointestinal (UGI) cancers in a cohort of 469,448 people in the US, ages 50-71 at baseline. Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for diabetes and UGI cancers, controlling for multiple potential confounders, including body mass index (BMI).
Results
We observed no association of self-reported diabetes with risk of EADC, HR (95%CI) = 0.98 (0.73-1.31), esophageal squamous cell carcinoma (ESCC), HR (95%CI) = 1.02 (0.60-1.74), or GNCA, HR (95%CI) = 0.98 (0.70-1.37). However, diabetes was significantly associated with an increased risk of GCA, HR (95%CI) = 1.89 (1.43-2.50). The significant association between diabetes and risk of GCA remained after adjustment for BMI, HR (95%CI) = 1.70 (1.28-2.26) and did not differ by BMI strata (pinteraction =0.83). The significant association was unchanged when restricting to only overweight subjects (BMI 25 - ≤30), HR (95%CI) = 1.83 (1.18-2.85).
Conclusions
We found a significant association between self-reported diabetes and increased risk of GCA.
Impact
Our results suggest that the metabolic and hormonal changes related to diabetes may play a role in the etiology of GCA independently from BMI.
doi:10.1158/1055-9965.EPI-10-1244
PMCID: PMC3089699  PMID: 21415356
Esophageal adenocarcinoma; gastric adenocarcinoma; diabetes; BMI
12.  The Relationship Between Serum Ghrelin and the Risk of Gastric and Esophagogastric Junctional Adenocarcinomas 
Background
Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated.
Methods
We conducted a nested case–control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric noncardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided.
Results
Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements.
Conclusion
Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis.
doi:10.1093/jnci/djr194
PMCID: PMC3139586  PMID: 21693726
13.  Accuracy of screening for gastric cancer using serum pepsinogen concentrations 
Gut  1999;44(5):693-697.
BACKGROUND/AIMS—The characteristics of pepsinogen screening for gastric cancer were investigated to establish a suitable cut off point for identifying gastric cancer, using endoscopic diagnosis as the yardstick. 
SUBJECTS/METHODS—Serum pepsinogen concentrations were measured in 5113 subjects who were also screened for gastric cancer by endoscopy. The cut off point for pepsinogen was determined using receiver operator characteristics curves. 
RESULTS—The most suitable cut off point was a pepsinogen I concentration of less than 70 ng/ml and a ratio of pepsinogen I to pepsinogen II of less than 3.0. Using this cut off point, the sensitivity and specificity of pepsinogen screening for gastric cancer were 84.6% and 73.5% respectively. All cases of gastric cancer in patients with severe atrophic gastritis were detected. However, two of four cases of gastric cancer in patients with mild atrophic gastritis were overlooked. In subjects with mild atrophic gastritis, when gastric cancer arises within the fundic gland region, the size of the lesion determines whether it is possible to detect cancer by serum pepsinogen screening. 
CONCLUSION—Pepsinogen screening has many advantages, including its suitability for combination with other screening methods because it is simple and inexpensive. 


Keywords: pepsinogen; gastric cancer; screening; cut off point; receiver operator characteristics curves; atrophic gastritis
PMCID: PMC1727514  PMID: 10205207
14.  A prospective study of BMI and risk of esophageal and gastric adenocarcinoma 
The incidence of esophageal adenocarcinoma (EADC) is rapidly increasing in Western countries and obesity is thought to be a major risk factor. We examined the association between BMI and EADC, gastric cardia adenocarcinoma, and gastric noncardia adenocarcinoma in a cohort of approximately 500,000 people in the US. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) with control for many potential confounders. We found that compared to people with a BMI of 18.5-25 Kg/m2, a BMI ≥35 was associated with significantly increased risk of EADC, HR (95% CI) = 2.27 (1.44-3.59), and gastric cardia adenocarcinoma 2.46 (1.60-3.80), but not gastric noncardia adenocarcinoma 0.84 (0.50-1.42). Using nonlinear models, we found that higher BMI was associated with increased risk of EADC even within the normal BMI. Increased adiposity was associated with higher risk of EADC even within the normal weight range.
doi:10.1016/j.ejca.2007.12.009
PMCID: PMC2350215  PMID: 18221867
Esophageal adenocarcinoma; Gastric adenocarcinoma; Obesity; BMI; Prospective; Cohort
15.  Predominant mucosal IL-8 mRNA expression in non-cagA Thais is risk for gastric cancer 
AIM: To study gastric mucosal interleukine-8 (IL-8) mRNA expression, the cytotoxin-associated gene A (cagA) mutation, and serum pepsinogen (PG) I/II ratio related risk in Thai gastric cancer.
METHODS: There were consent 134 Thai non-cancer volunteers who underwent endoscopic narrow band imaging examination, and 86 Thais advance gastric cancer patients who underwent endoscopic mucosal biopsies and gastric surgery. Tissue samples were taken by endoscopy with 3 points biopsies. The serum PG I, II, and Helicobacter pylori (H. pylori) immunoglobulin G (IgG) antibody for H. pylori were tested by enzyme-linked immunosorbent assay technique. The histopathology description of gastric cancer and non-cancer with H. pylori detection was defined with modified Sydney Score System. Gastric mucosal tissue H. pylori DNA was extracted and genotyped for cagA mutation. Tissue IL-8 and cyclooxygenase-2 (COX-2) mRNA expression were conducted by real time relative quantitation polymerase chain reaction. From 17 Japanese advance gastric cancer and 12 benign gastric tissue samples, all were tested for genetic expression with same methods as well as Thai gastric mucosal tissue samples. The multivariate analysis was used for the risk study. Correlation and standardized t-test were done for quantitative data, P value < 0.05 was considered as a statistically significant.
RESULTS: There is a high non cagA gene of 86.8 per cent in Thai gastric cancer although there are high yields of the East Asian type in the positive cagA. The H. pylori infection prevalence in this study is reported by combined histopathology and H. pylori IgG antibody test with 77.1% and 97.4% of sensitivity and specificity, respectively. The serum PG I/II ratio in gastric cancer is significantly lower than in the non-cancer group, P = 0.045. The serum PG I/II ratio of less than 3.0 and IL-8 mRNA expression ≥ 100 or log10 ≥ 2 are significant cut off risk differences between Thai cancer and non-cancer, P = 0.03 and P < 0.001, respectively. There is a significantly lower PGI/II ratio in Japanese than that in Thai gastric cancer, P = 0.026. Serum PG I/II ratio at cut off less than 3.0 and IL-8 mRNA expression Raw RQ > 100 or log10 > 2 are significantly difference between Thai cancer group when compared to non-cancer group, P = 0.013 and P < 0.001, respectively. In the correlation study, low PG I/II ratio does not associate with chronic atrophic gastritis severity score in Thais non-cancer cases. However, there is a trend, but not significant convert correlation between IL-8 mRNA expression level and low PG I/II ratio in Thai positive H. pylori infection. The high expression of IL-8 gene demonstrates a poorer prognosis by stage and histology.
CONCLUSION:Predominant gastric mucosal IL-8 mRNA expression level, H. pylori infection, and low PG I/II ratio are relative risks for Thai gastric cancer without correlation with cagA mutation.
doi:10.3748/wjg.v19.i19.2941
PMCID: PMC3660819  PMID: 23704827
Gastric cancer; CagA mutation; Interleukine-8 mRNA expression; Helicobacter pylori; Pepsinogen I/II ratio
16.  Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis 
PLoS ONE  2011;6(10):e26957.
Background
To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study.
Methods
We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology.
Results
309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 µg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 µg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3).
Conclusions
Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
doi:10.1371/journal.pone.0026957
PMCID: PMC3204997  PMID: 22066020
17.  Serum pepsinogens and Helicobacter pylori in relation to the risk of esophageal squamous cell carcinoma in the ATBC Study 
Background
Helicobacter pylori (H. pylori) can induce gastric atrophy in humans, which in turn increases gastric cancer risk. Whether H. pylori and gastric atrophy also affect the risk of esophageal squamous cell carcinoma (ESCC), however, remains unresolved.
Methods
We performed a nested case-control study within the prospective ATBC Study to assess these relationships. The ATBC Study is composed of 29,133 Finnish male smokers, aged 50–69, who were recruited during 1985–1988. Using baseline sera, we assessed H. pylori status (via IgG antibodies against whole-cell and CagA antigens) and gastric atrophy status (via the biomarkers pepsinogen I (PGI) and II (PGII)) in 79 ESCC cases and 94 controls. Logistic regression with adjustment for age, date of blood draw, education, cigarette smoking, alcohol, body mass index, and fruit and vegetable intake was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI).
Results
Gastric atrophy (PGI:PGII <4) was associated with ESCC (OR=4.58, 95%CI:2.00–10.48). There was no evidence for an association between H. pylori and ESCC (OR=0.94, 95%CI:0.40–2.24).
Conclusions
These results could be explained by misclassification of H. pylori status due to serologic amnesia, ESCC risk being dependent upon the functional consequences or interactions of H. pylori, rather than the infection per se, gastric atrophy having a different histogenesis in ESCC without being primarily dependent upon H. pylori acquisition, or a lack of statistical power to detect an effect.
Impact
Validation of these results may warrant mechanistic studies to determine the route of association between gastric atrophy and ESCC.
doi:10.1158/1055-9965.EPI-10-0270
PMCID: PMC2919643  PMID: 20647397
Atrophy; Esophageal Neoplasms; Helicobacter pylori; Nested Case-Control Studies; Pepsinogens; Prospective Studies
18.  Contribution of H. pylori and Smoking Trends to US Incidence of Intestinal-Type Noncardia Gastric Adenocarcinoma: A Microsimulation Model 
PLoS Medicine  2013;10(5):e1001451.
Jennifer Yeh and colleagues examine the contribution of IHelicobacter pyloriI and smoking trends to the incidence of past and future intestinal-type noncardia gastric adenocarcinoma.
Please see later in the article for the Editors' Summary
Background
Although gastric cancer has declined dramatically in the US, the disease remains the second leading cause of cancer mortality worldwide. A better understanding of reasons for the decline can provide important insights into effective preventive strategies. We sought to estimate the contribution of risk factor trends on past and future intestinal-type noncardia gastric adenocarcinoma (NCGA) incidence.
Methods and Findings
We developed a population-based microsimulation model of intestinal-type NCGA and calibrated it to US epidemiologic data on precancerous lesions and cancer. The model explicitly incorporated the impact of Helicobacter pylori and smoking on disease natural history, for which birth cohort-specific trends were derived from the National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS). Between 1978 and 2008, the model estimated that intestinal-type NCGA incidence declined 60% from 11.0 to 4.4 per 100,000 men, <3% discrepancy from national statistics. H. pylori and smoking trends combined accounted for 47% (range = 30%–58%) of the observed decline. With no tobacco control, incidence would have declined only 56%, suggesting that lower smoking initiation and higher cessation rates observed after the 1960s accelerated the relative decline in cancer incidence by 7% (range = 0%–21%). With continued risk factor trends, incidence is projected to decline an additional 47% between 2008 and 2040, the majority of which will be attributable to H. pylori and smoking (81%; range = 61%–100%). Limitations include assuming all other risk factors influenced gastric carcinogenesis as one factor and restricting the analysis to men.
Conclusions
Trends in modifiable risk factors explain a significant proportion of the decline of intestinal-type NCGA incidence in the US, and are projected to continue. Although past tobacco control efforts have hastened the decline, full benefits will take decades to be realized, and further discouragement of smoking and reduction of H. pylori should be priorities for gastric cancer control efforts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cancer of the stomach (gastric cancer) is responsible for a tenth of all cancer deaths world-wide, with an estimated 700,000 people dying from this malignancy every year, making it the second most common cause of global cancer-related deaths after lung cancer. Unfortunately, the projected global burden of this disease estimate that deaths from gastric cancer will double by 2030. Gastric cancer has a poor prognosis with only a quarter of people with this type of cancer surviving more than five years. In order to reduce deaths, it is therefore of utmost importance to identify and reduce the modifiable risk factors associated with gastric cancer. Smoking and chronic gastric infection with the bacteria Helicobacter pylori (H. pylori), are known to be two common modifiable risk factors for gastric cancer, particularly for a type of gastric cancer called intestinal-type noncardia gastric adenocarcinoma (NCGA), which occurs at the distal end of the stomach and accounts for more than half of all cases of gastric cancer in US men.
Why Was This Study Done?
H. pylori initiates a precancerous process, and so infection with this bacteria can increase intestinal-type NCGA risk by as much as 6-fold while smoking doubles cancer risk by advancing increasing progression of existing lesions. Changes in these two risk factors over the past century (especially following the US Surgeon General's Report on Smoking and Health in 1964) have led to a dramatic decline in the rates of gastric cancer in US men. Understanding the combined effects of underlying risk factor trends on health outcomes for intestinal-type NCGA at the population level can help to predict future cancer trends and burden in the US. So in this study, the researchers used a mathematical model to estimate the contribution of H. pylori and smoking trends on the decline in intestinal-type NCGA incidence in US men.
What Did the Researchers Do and Find?
The researchers used birth cohorts derived from data in two national databases, the National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS) to develop a population-based model of intestinal-type NCGA. To ensure model predictions were consistent with epidemiologic data, the researchers calibrated the model to data on cancer and precancerous lesions and using the model, projected population outcomes between 1978 and 2040 for a base-case scenario (in which all risk factor trends were allowed to vary over time). The researchers then evaluated alternative risk factors scenarios to provide insights on the potential benefit of past and future efforts to control gastric cancer.
Using these methods, the researchers estimated that the incidence of intestinal-type NCGA (standardized by age) fell from 11.0 to 4.4 per 100,000 men between 1978 and 2008, a drop of 60%. When the researchers incorporated only H. pylori prevalence and smoking trends into the model (both of which fell dramatically over the time period) they found that intestinal-type NCGA incidence fell by only 28% (from 12.7 to 9.2 per 100,000 men), suggesting that H. pylori and smoking trends are responsible for 47% of the observed decline. The researchers found that H. pylori trends alone were responsible for 43% of the decrease in cancer but smoking trends were responsible for only a 3% drop. The researchers also found evidence that after the 1960s, observed trends in lower smoking initiation and higher cessation accelerated the decline in intestinal-type NCGA incidence by 7%. Finally, the researchers found that intestinal-type NCGA incidence is projected to decline an additional 47% between 2008 and 2040 (4.4 to 2.3 per 100,000 men) with H. pylori and smoking trends accounting for more than 80% of the observed fall.
What Do These Findings Mean?
These findings suggest that, combined with a fall in smoking rates, almost half of the observed fall in rates of intestinal-type NCGA cancer in US men between 1978 and 2008 was attributable to the decline in infection rates of H. pylori. Rates for this cancer are projected to continue to fall by 2040, with trends for both H. pylori infection and smoking accounting for more than 80% of the observed fall, highlighting the importance of the relationship between risk factors changes over time and achieving long-term reduction in cancer rates. This study is limited by the assumptions made in the model and in that it only examined one type of gastric cancer and excluded women. Nevertheless, this modeling study highlights that continued efforts to reduce rates of smoking and H. pylori infection will help to reduce rates of gastric cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001451.
The National Cancer Institute gives detailed information about gastric cancer
The Gastric Cancer Foundation has information on gastric cancer for patients and professionals
Cancer Research UK explains types of gastric cancer
doi:10.1371/journal.pmed.1001451
PMCID: PMC3660292  PMID: 23700390
19.  Low Levels of Pepsinogen I and Pepsinogen I/II Ratio are Valuable Serologic Markers for Predicting Extensive Gastric Corpus Atrophy in Patients Undergoing Endoscopic Mucosectomy 
Gut and Liver  2010;4(4):475-480.
Background/Aims
The levels of pepsinogen (PG) I and the PGI/II ratio are useful serologic markers for chronic atrophic gastritis. This study evaluated the performance and clinical implications of these markers in patients undergoing endoscopic mucosectomy.
Methods
We enrolled 142 consecutive patients with early gastric tumors and Helicobacter pylori infection who were eligible for mucosectomy. Chronic gastritis and atrophy were assessed using four defined biopsy procedures. Serum PGs were measured by an enzyme immunoassay. Optimal diagnostic cut-offs and performance were determined using receiver operating characteristic curves.
Results
The PGI level and the PGI/II ratio decreased with corpus-dominant gastritis and as atrophy advanced toward the corpus greater curvature (GC). For the presence of corpus GC atrophy, the areas under the PGI and PGI/II-ratio curves were 0.82 and 0.77, respectively. The optimal cut-off levels were 59.3µg/L for PGI (sensitivity, 83.3%; specificity, 78.4%) and 3.6µg/L for PGI/II ratio (sensitivity, 70.0%; specificity, 78.4%). Using these serologic cut-off levels, we found that the frequency of corpus tumor location differed significantly (32.9% vs 11.1% for PGI <59.3 and ≥59.3µg/L, respectively; and 31.1% vs 14.8% for PGI/II ratio <3.5 and ≥3.5, respectively; p<0.05).
Conclusions
A low PGI level and PGI/II ratio are valuable serologic markers for predicting corpus GC atrophy, and have clinical implications with respect to the corpus location of tumors in mucosectomy patients.
doi:10.5009/gnl.2010.4.4.475
PMCID: PMC3021602  PMID: 21253295
Pepsinogens; Atrophic gastritis; Stomach neoplasia; Helicobacter pylori; Endoscopy
20.  Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP Diet and Health study 
The aim of this study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric non-cardia adenocarcinoma. From 1995–1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric non-cardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Though apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null (e.g. EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95%CI) 1.66 (1.27–2.18) P for trend <0.01; EAC multivariate adjusted HR (95%CI) 1.17 (0.84–1.64) P for trend=0.58). Similar patterns were also observed for fat subtypes (e.g. EAC saturated fat, energy adjusted HR (95%CI) 1.79 (1.37–2.33) P for trend <0.01; EAC saturated fat, multivariate adjusted HR (95%CI) 1.27 (0.91–1.78) P for trend=0.28). However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5–<25 kg/m2) (HR (95%CI) 0.76 (0.63–0.92)), that was not present in overweight subjects (HR (95%CI) 1.04 (0.96–1.14)), or in unstratified analysis (HR (95%CI) 0.97 (0.90–1.05)). P for interaction=0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; though a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.
doi:10.1002/ijc.27366
PMCID: PMC3346853  PMID: 22116732
cohort; dietary fat; esophageal neoplasms; stomach neoplasms; prospective
21.  Serum pepsinogen II is a better diagnostic marker in gastric cancer 
AIM: To investigate screening makers for gastric cancer, we assessed the association between gastric cancer and serum pepsinogens (PGs).
METHODS: The subjects comprised 450 patients with gastric cancer, 111 individuals with gastric atrophy, and 961 healthy controls. Serum anti-Helicobacter pylori (H. pylori) immunoglobulin G (IgG), PGIand PG II were detected by enzyme-linked immunosorbent assay. Gastric atrophy and gastric cancer were diagnosed by endoscopy and histopathological examinations. Odds ratios and 95%CIs were calculated using multivariate logistic regression.
RESULTS: Rates of H. pylori infection remained high in Northeastern China. Rates of H. pylori IgG positivity were greater in the gastric cancer and gastric atrophy groups compared to the control group (69.1% and 75.7% vs 49.7%, P < 0.001). Higher levels of PG II (15.9 μg/L and 13.9 μg/L vs 11.5 μg/L, P < 0.001) and lower PGI/PG II ratio (5.4 and 4.6 vs 8.4, P < 0.001) were found in patients with gastric cancer or gastric atrophy compared to healthy controls, whereas no correlation was found between the plasma PGIconcentration and risk of gastric cancer (P = 0.537). In addition, multivariate logistic analysis indicated that H. pylori infection and atrophic gastritis were independent risk factors for gastric cancer. Lower plasma PGI/PG II ratio was associated with higher risks of atrophy and gastric cancer. Furthermore, plasma PG II level significantly correlated with H. pylori-infected gastric cancer.
CONCLUSION: Serum PG II concentration and PGI/PG II ratio are potential biomarkers for H. pylori-infected gastric disease. PG II is independently associated with risk of gastric cancer.
doi:10.3748/wjg.v18.i48.7357
PMCID: PMC3544042  PMID: 23326145
Gastric cancer; Pepsinogens; Helicobacter pylori; Gastric atrophy; Screening
22.  Tea, coffee, carbonated soft drinks and upper gastrointestinal tract cancer risk in a large United States prospective cohort study 
The authors investigated the relationship between hot tea, iced tea, coffee and carbonated soft drinks consumption and upper gastrointestinal tract cancers risk in the NIH-AARP Study. During 2,584,953 person-years of follow-up on 481,563 subjects, 392 oral cavity, 178 pharynx, 307 larynx, 231 gastric cardia, 224 gastric noncardia cancer, 123 esophageal squamous cell carcinoma (ESCC) and 305 esophageal adenocarcinoma (EADC) cases were accrued. Hazard ratios (HRs) and 95% Confidence Intervals (95%CIs) were calculated by multivariate-adjusted Cox regression. Compared to non-drinking, the hazard ratio for hot tea intake of ≥1 cup/day was 0.37 (95%CI: 0.20, 0.70) for pharyngeal cancer. The authors also observed a significant association between coffee drinking and risk of gastric cardia cancer (compared to <1 cup/day, the hazard ratio for drinking >3 cups/day was 1.57 (95%CI: 1.03, 2.39)), and an inverse association between coffee drinking and EADC for the cases occurring in the last three years of follow-up (compared to <1 cup/day, the hazard ratio for drinking >3 cups/day was 0.54 (95%CI: 0.31, 0.92)), but no association in earlier follow-up. In summary, hot tea intake was inversely associated with pharyngeal cancer, and coffee was directly associated with gastric cardia cancer, but was inversely associated with EADC during some follow-up periods.
doi:10.1016/j.ejca.2010.03.025
PMCID: PMC2891563  PMID: 20395127
tea; coffee; carbonated beverages; upper gastrointestinal tract; cancer
23.  A Prospective Study of Vitamin and Mineral Supplement Use and the Risk of Upper Gastrointestinal Cancers 
PLoS ONE  2014;9(2):e88774.
We examined the association of use of multivitamins or single vitamin/mineral supplements with risk of four upper gastrointestinal cancers in the NIH-AARP Diet and Health Study cohort with 11 years of follow-up. After exclusions, 490,593 persons were included in our analytic cohort and 1780 upper gastrointestinal cancers were accrued. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox models with adjustment for potential confounders. We observed no significant associations between multivitamin use and risk for the four cancer outcomes in crude or adjusted models. Among individual vitamin or mineral supplements, use of iron supplements was associated with significantly lower risk of esophageal adenocarcinoma (HR = 0.68, 95% CI = 0.49 to 0.94) and a significantly increased risk of gastric noncardia adenocarcinoma (HR = 1.59, 95% CI = 1.24 to 2.05). For gastric noncardia adenocarcinoma, we saw associations with zinc use (HR = 1.28, 95% CI = 1.01 to 1.62) and vitamin C use (HR = 0.79 95% CI = 0.65 to 0.96). Calcium use, some of which was reported as antacids and used to treat reflux disease, was associated with higher risk of esophageal adenocarcinoma (HR = 1.27, 95% CI = 1.06 to 1.52) and gastric cardia adenocarcinoma (HR = 1.27, 95% CI = 1.03 to 1.56) cancers. We saw no evidence that multivitamin use was associated with reduced risk of four highly fatal upper gastrointestinal cancers, but there were some differences in risk with reported use of individual supplements.
doi:10.1371/journal.pone.0088774
PMCID: PMC3928299  PMID: 24558423
24.  Physical Activity and Esophageal and Gastric Carcinoma in a Large Prospective Study 
Background
Few studies have investigated the relationship of physical activity to esophageal and gastric carcinoma according to histology and anatomic site.
Methods
This study prospectively investigated the association between physical activity and esophageal and gastric carcinoma in a cohort of 487,732 U.S. men and women, followed from 1995–1996 to December 31, 2003. All analyses were performed in 2007– 2008.
Results
During 8 years of follow-up study, 523 cases of esophageal carcinoma (149 squamous cell and 374 adenocarcinoma) and 642 cases of gastric carcinoma (313 cardia and 329 noncardia) were documented. Physical activity was associated with reduced risk of esophageal and gastric adenocarcinomas but was unrelated to esophageal squamous cell carcinoma. The inverse association with physical activity was strongest for gastric noncardia adenocarcinoma (multivariate relative risk [RR] for highest versus lowest physical activity level=0.62, 95% CI=0.44, 0.87). Relationships were weaker but evident for gastric cardia adenocarcinoma (RR=0.83; 95% CI=0.58, 1.19) and esophageal adenocarcinoma (RR=0.75; 95% CI=0.53, 1.06). No significant relationship with physical activity was observed for esophageal squamous cell carcinoma (RR=1.05; 95% CI=0.64, 1.74). Exclusion of cases diagnosed during the first 2 follow-up years did not change those estimates, indicating that the findings are not due to decreased activity levels among participants with undiagnosed cancer at entry.
Conclusions
Physical activity may play a role in the prevention of upper gastrointestinal tract adenocarcinomas. No association was seen between physical activity and esophageal squamous cell carcinoma.
doi:10.1016/j.amepre.2008.09.033
PMCID: PMC2655147  PMID: 19062237
25.  PLCE1 mRNA and protein expression and survival of patients with esophageal squamous cell carcinoma and gastric adenocarcinoma 
Background
Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival.
Methods
PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n=132), gastric cardia adenocarcinoma (GCA, n=62) and gastric noncardia adenocarcinoma (GNCA, n=72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n=303), and tumors of GCA (n=298) and GNCA (n=124).
Results
Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P=0.03, probe_205112_at), as well as in GCA and GNCA tumors (P<0.0001, each probe). Protein expression was non-significantly reduced in ESCC tumors (P=0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs lowest quartile; P-trend=0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; P-trend=0.04), but not for GNCA cases (P=0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; P-trend=0.04).
Conclusions
Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression appears to be associated with cancer prognosis.
Impact
A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation.
doi:10.1158/1055-9965.EPI-13-1329
PMCID: PMC4207376  PMID: 24867265

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