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1.  Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients 
AIM: To investigate the expression of p53 and p21 and associations with possible risk factors, such as cigarette smoking, in esophageal squamous cell carcinoma (ESCC) in northeastern Iran, a region with a high incidence of ESCC.
METHODS: The expression of p53 and p21 proteins was investigated immunohistochemically in tumor tissue from 80 ESCC patients and in 60 available paraffin-embedded blocks of adjacent normal specimens from the cases, along with normal esophageal tissue from 80 healthy subjects.
RESULTS: Positive expression of p53 protein was detected in 56.2% (45/80) of ESCC cases, and in none of the normal esophageal tissue of the control group (P < 0.001). Furthermore, 73.8% (59/80) of ESCC cases and 43.8% (35/80) of controls had positive expression of p21 protein (P < 0.001). Cigarette smoking was significantly associated with p53 over-expression in ESCC cases (P = 0.010, OR = 3.64; 95% CI: 1.32-10.02). p21 over-expression was associated with poorer clinical outcome among the ESCC patients (P = 0.009).
CONCLUSION: Over-expression of p53 in association with cigarette smoking may play a critical role in ESCC carcinogenesis among this high-risk population of northeastern Iran. Furthermore, p21 over-expression was found to be associated with poor prognosis, specifically in the operable ESCC patients.
PMCID: PMC2957605  PMID: 20954283
Esophageal squamous cell carcinoma; p53; p21; Immunohistochemistry; Survival; Smoking
2.  PAH exposure in esophageal tissue and risk of esophageal squamous cell carcinoma in northeastern Iran 
Gut  2010;59(9):1178-1183.
To evaluate the association of polycyclic aromatic hydrocarbon (PAH) exposure in esophageal epithelial tissue and esophageal squamous cell carcinoma (ESCC) case status in an ESCC case-control study in a high-risk population in northeastern Iran.
Immunohistochemical staining of tissue microarrays (TMAs) of non-tumoral esophageal biopsies from ESCC cases and control subjects. Immunohistochemistry was performed using monoclonal antibodies 8E11 and 5D11, raised against benzo[a]pyrene (B[a]P) diol epoxide (BPDE)-I-modified guanosine and BPDE-I-modified DNA, respectively. Staining intensity was quantified by image analysis, and the average staining in three replicates was calculated.
Rural region in northeastern Iran.
Cases were patients with biopsy-proven ESCC. Controls were GI clinic patients with no endoscopic or biopsy evidence of ESCC.
Main outcome measure
Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between antibody staining intensity and ESCC case status.
Cultured ESCC cells exposed to B[a]P in vitro showed dose-dependent staining with 8E11, but not with 5D11. With 8E11, sufficient epithelial tissue was available in the TMA cores to analyze 91 cases and 103 controls. Compared to the lowest quintile of 8E11 staining in the controls, adjusted ORs (95% CIs) for the 2nd to 5th quintiles were 2.42, 5.77, 11.3, and 26.6 (5.21–135), respectively (P for trend < 0.001). With 5D11, 89 cases and 101 controls were analyzed. No association between staining and case status was observed (ORs (95% CIs) for the 2nd to 5th quintiles were 1.26, 0.88, 1.06, and 1.63 (0.63–4.21), P for trend = 0.40).
Dramatically higher levels of 8E11 staining were observed in non-tumoral esophageal epithelium from ESCC patients than from control subjects. This finding strengthens the evidence for a causal role for PAHs in esophageal carcinogenesis in northeastern Iran.
PMCID: PMC3505022  PMID: 20584779
esophageal squamous cell carcinoma; polycyclic aromatic hydrocarbons; immunohistochemistry; tissue microarray
3.  Predicting esophageal squamous cell carcinoma and squamous dysplasia: risk modeling in a high risk area in Iran 
Archives of Iranian Medicine  2012;15(1):18-21.
Identifying people at higher risk of having squamous dysplasia, the precursor lesion for esophageal squamous cell carcinoma (ESCC), would allow targeted endoscopic screening.
We used multivariate logistic regression models to predict ESCC and dysplasia as outcomes. The ESCC model was based on data from the Golestan Case-Control Study (total n=871; cases=300), and the dysplasia model was based on data from a cohort of subjects from a GI clinic in Northeast Iran (total n=724; cases=26). In each of these analyses, we fit a model including all risk factors known in this region to be associated with ESCC. Individual risks were calculated using the linear combination of estimated regression coefficients and individual-specific values for covariates. We used cross-validation to determine the area under the curve (AUC) and to find the optimal cut points for each of the models.
The model had an area under the curve of 0.77 (95% CI: 0.74–0.80) to predict ESCC with 74% sensitivity and 70.4% specificity for the optimum cut point. The area under the curve was 0.71 (95% CI: 0.64–0.79) for dysplasia diagnosis, and the classification table optimized at 61.5% sensitivity and 69.5% specificity. In this population, the positive and negative predictive values for diagnosis of dysplasia were 6.8% and 97.8%, respectively.
Our models were able to discriminate between ESCC cases and controls in about 77%, and between individuals with and without squamous dysplasia in about 70% of the cases. Using risk factors to predict individual risk of ESCC or squamous dysplasia still has limited application in clinical practice, but such models may be suitable for selecting high risk individuals in research studies, or increasing the pretest probability for other screening strategies.
PMCID: PMC3294378  PMID: 22208438
4.  Etiological study of esophageal squamous cell carcinoma in an endemic region: a population-based case control study in Huaian, China 
BMC Cancer  2006;6:287.
Continuous exposure to various environmental carcinogens and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) are associated with many types of human cancers, including esophageal squamous cell carcinoma (ESCC). Huaian, China, is one of the endemic regions of ESCC, but fewer studies have been done in characterizing the risk factors of ESCC in this area. The aims of this study is to evaluate the etiological roles of demographic parameters, environmental and food-borne carcinogens exposure, and XME polymorphisms in formation of ESCC, and to investigate possible gene-gene and gene-environment interactions associated with ESCC in Huaian, China.
A population based case-control study was conducted in 107 ESCC newly diagnosed cases and 107 residency- age-, and sex-matched controls in 5 townships of Huaian. In addition to regular epidemiological and food frequency questionnaire analyses, genetic polymorphisms of phase I enzymes CYP1A1, CYP1B1, CYP2A6, and CYP2E1, and phase II enzymes GSTM1, GSTT1, GSTP1, and microsomal epoxide hydrolase (EPHX) were assessed from genomic DNA using PCR based techniques.
Consuming acrid food, fatty meat, moldy food, salted and pickled vegetables, eating fast, introverted personality, passive smoking, a family history of cancer, esophageal lesion, and infection with Helicobacter pylori were significant risk factors for ESCC (P < 0.05). Regular clean up of food storage utensils, green tea consumption, and alcohol abstinence were protective factors for ESCC (P < 0.01). The frequency of the GSTT1 null genotype was higher in cases (59.4%) compared to controls (47.2%) with an odds ratio (OR) of 1.68 and 95% confidence interval (CI) from 0.96 to 2.97 (P = 0.07), especially in males (OR = 2.78; 95% CI = 1.22–6.25; P = 0.01). No associations were found between polymorphisms of CYP1A1, CYP1B1, CYP2A6, CYP2E1, GSTM1, GSTP1, and EPHX and ESCC (P > 0.05).
Our results demonstrated that dietary and environmental exposures, some demographic parameters and genetic polymorphism of GSTT1 may play important roles in the development of ESCC in Huaian area, China.
PMCID: PMC1774575  PMID: 17173682
5.  Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran 
Nutrition Journal  2011;10:137.
Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factors that may contribute to this high incidence have not been thoroughly studied. The aim of this study was to evaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC.
In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewed and usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeled through unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration), physical activity, and education.
ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals, compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increased significantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13], discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intake reduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5 times higher selenium, 5.48 times as much β-carotene and 1.98 times as much α-tocopherol as the amount ESCC cases consumed.
This study suggests that high intake of nutrients primarily found in plant-based foods is associated with a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play major roles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophageal cancer in Iran, and perhaps other high-risk regions.
PMCID: PMC3260093  PMID: 22185224
Esophageal squamous cell carcinoma; macronutrients; vitamins; minerals; Iran
6.  Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran 
PLoS ONE  2011;6(12):e29488.
Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC.
Methodology/Principal Findings
Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence.
ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.
PMCID: PMC3246475  PMID: 22216294
7.  Poor Dental Status and Oral Hygiene Practices in Institutionalized Older People in Northeast Brazil 
In this study we describe the dental status and oral hygiene practices in institutionalized older people and identify factors associated with poor dental status. A cross-sectional study was performed in a nursing home in Fortaleza, the capital of Ceará State (northeast Brazil). The number of decayed, missing, and filled teeth (DMFT) was assessed in the residents of the nursing home (n = 167; mean age = 76.6 years). The mean DMFT value was 29.7; the mean number of missing teeth was 28.4. Ninety-three (58.1%) were edentulous. Almost 90% practiced oral hygiene, but only about half used a toothbrush. Only 8% had visited a dentist in the preceding three months. Most of the variables regarding oral hygiene habits (such as the use of toothbrush, frequency of oral hygiene per day, regular tooth brushing after meals) did not show any significant association with the DMFT. In multivariate regression analysis, age, general literacy level, and practice of oral hygiene were independently associated with the DMFT (R2 = 0.13). Institutionalized older people in northeast Brazil have poor dental status, and oral hygiene practices are insufficient. Dental health education is needed focusing on the special needs of this neglected and socioeconomically deprived population to improve their quality of life.
PMCID: PMC2836820  PMID: 20339459
8.  Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma 
Poor oral health and tooth loss have been proposed as possible risk factors for some chronic diseases, including gastric cancer. However only a small number of studies have tested these associations.
We conducted a case-control study in Golestan Province, Iran, that enrolled 309 cases diagnosed with gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-locations) and 613 sex, age and neighborhood matched controls. Data on oral health were obtained through physical examination and questionnaire including tooth loss, the number of decayed, missing, and filled teeth, and frequency of tooth brushing. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models adjusted for potential confounders. Standard one degree-of-freedom linear trend test and a multiple degree of freedom global test of the effect of adding oral hygiene variables to the model were also calculated.
Our results showed apparent associations between tooth loss and DMFT score with risk of gastric cancer, overall and at each anatomic subsite. However, these associations were not monotonic and were strongly confounded by age. The results also showed that subjects who brushed their teeth less than daily were at significantly higher risk for gastric cardia adenocarcinoma OR (95% CI) of 5.6 (1.6–19.3).
We found evidence for an association between oral health and gastric cancer, but the non- monotonic association, the relatively strong effect of confounder adjustment, and inconsistent results across studies must temper the strength of any conclusions.
PMCID: PMC3644330  PMID: 23503651
Adenocarcinoma; Tooth loss; Oral health; Stomach
9.  Squamous cell carcinoma in Barrett’s esophagus: field effect versus metastasis 
Barrett’s esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE.
PMCID: PMC3568520  PMID: 22221671
adenocarcinoma; Barrett’s esophagus; squamous cell carcinoma
10.  Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma 
Carcinogenesis  2013;34(5):1062-1068.
In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.
PMCID: PMC3643422  PMID: 23358850
11.  N-acetyltransferase 2 Polymorphisms and Risk of Esophageal Cancer in a Chinese Population 
PLoS ONE  2014;9(2):e87783.
Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Genetic factors might play an important role in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). We conducted a hospital-based case-control study to evaluate ten NAT2 tagging single nucleotide polymorphisms (SNPs) on the risk of ESCC. Six hundred and twenty-nine ESCC cases and 686 controls were recruited. Their genotypes were determined using the ligation detection reaction method. In the single locus analyses, there was a borderline statistically significant difference in genotype frequencies of NAT2 rs1565684 T>C SNP between the cases and the controls (p = 0.057). The NAT2 rs1565684 CC genotype was associated with a borderline significantly increased risk for ESCC (CC vs. TT: adjusted OR = 1.77, 95% CI = 0.97–3.21, p = 0.063 and CC vs. TT/TC: adjusted OR = 1.68, 95% CI = 0.93–3.04, p = 0.085). The association was evident among older patients and patients who never drunk. After the Bonferroni correction, in all comparison models, NAT2 rs1565684 T>C SNP was not associated with ESCC risk (p>0.05). For the other nine NAT2 SNPs, after Bonferroni correction, in all comparison models, the nine SNPs were also not associated with ESCC risk (p>0.05). Thus, nine NAT2 tagging SNPs were not associated with risk of ESCC. NAT2 rs1565684 T>C SNP might play a slight role in ESCC etiology. Additional, larger studies and tissue-specific biological characterization are required to confirm the current findings.
PMCID: PMC3929587  PMID: 24586291
12.  p21 rs3176352 G>C and p73 rs1801173 C>T Polymorphisms Are Associated with an Increased Risk of Esophageal Cancer in a Chinese Population 
PLoS ONE  2014;9(5):e96958.
Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Genetic factors might play an important role in esophageal squamous cell carcinoma (ESCC) carcinogenesis.
Designs and Methods
To evaluate the effect p21, p53, TP53BP1 and p73 single nucleotide polymorphisms (SNPs) on the risk of ESCC, we conducted a hospital based case–control study. A total of 629 ESCC cases and 686 controls were recruited. Their genotypes were determined using ligation detection reaction (LDR) method.
When the p21 rs3176352 GG homozygote genotype was used as the reference group, the CC genotype was associated with a significantly increased risk of ESCC. When the p73 rs1801173 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly increased risk of ESCC. After Bonferroni correction, for p21 rs3176352 G>C, the pcorrect was still significant. For the other six SNPs, in all comparison models, no association between the polymorphisms and ESCC risk was observed.
p21 rs3176352 G>C and p73 rs1801173 C>T SNPs are associated with increased risk of ESCC. To confirm the current findings, additional, larger studies and tissue-specific biological characterization are required.
PMCID: PMC4018405  PMID: 24820515
13.  Atrophic gastritis: Risk factor for esophageal squamous cell carcinoma in a Latin-American population 
AIM: To study the association between atrophic gastritis (AG) and esophageal squamous cell carcinoma (ESCC) in a Latin-America population.
METHODS: A case-control study was performed at two reference Brazilian hospitals including patients diagnosed with advanced ESCC and dyspeptic patients who had been subjected to upper gastrointestinal endoscopy, with biopsies of the gastric antrum and body. All cases with ESCC were reviewed by a single pathologist, who applied standard criteria for the diagnosis of mucosal atrophy, intestinal metaplasia, and dysplasia, all classified as AG. The data on the patients’ age, sex, smoking status, and alcohol consumption were collected from clinical records, and any missing information was completed by telephone interview. The association between AG and ESCC was assessed by means of univariate and multiple conditional logistic regressions.
RESULTS: Most patients were male, and the median age was 59 years (range: 37-79 years) in both the ESCC and control groups. Univariate analysis showed that an intake of ethanol greater than 32 g/d was an independent risk factor that increased the odds of ESCC 7.57 times (P = 0.014); upon multiple analysis, alcohol intake of ethanol greater than 32 g/d exhibited a risk of 4.54 (P = 0.081), as adjusted for AG and smoking. Smoking was shown to be an independent risk factor that increased the odds of ESCC 14.55 times (P = 0.011) for individuals who smoked 0 to 51 packs/year and 21.40 times (P = 0.006) for those who smoked more than 51 packs/year. Upon multiple analyses, those who smoked up to 51 packs/year exhibited a risk of 7.85 (P = 0.058), and those who smoked more than 51 packs/ year had a risk 11.57 times higher (P = 0.04), as adjusted for AG and alcohol consumption. AG proved to be a risk factor that increased the odds of ESCC 5.33 times (95%CI: 1.55-18.30, P = 0.008) according to the results of univariate conditional logistic regression.
CONCLUSION: There was an association by univariate conditional logistic regression between AG and ECSS in this sample of Latin-American population.
PMCID: PMC3623983  PMID: 23599625
Atrophic gastritis; Esophagus; Squamous cell carcinoma; Risk factor; Alcohol; Tobacco
14.  Association Between Gene Expression of Metabolizing Enzymes and Esophageal Squamous Cell Carcinomas in China 
Epidemiological studies have indicated that the incidence of esophageal squamous cell carcinoma (ESCC) is associated with environmental exposure to mutagens and carcinogens. To determine whether the basal expression level of genes involved in metabolism of carcinogens is associated with the risk of ESCC, a case–control study of 100 patients with newly diagnosed, untreated ESCC and 117 healthy controls was performed, and the relative expression levels of four metabolism genes (CYP2E1, GSTP1, MTHFR, and NQO1) were determined with quantitative real-time reverse transcription–polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). Analyzed with the mean of relative expression level in the controls as the cut-off point, the result exhibited that the increased risk for ESCC was significantly associated with reduced expression of GSTP1 (odds ratio [OR]=3.644, 95% confidence interval [CI: 1.947–6.823) and NQO1 (OR=1.870, 95% CI: 1.046–3.345). When adjusted for age, sex, smoking status, and alcohol use, the increased risk for ESCC was significantly associated with reduced expression of GSTP1, MTHFR, and NQO1, and GSTP1 mRNA showed a steady association with the risk for ESCC (OR=2.640) in the model of stepwise regression analysis. Reduced expression of GSTP1 in PBMCs was significantly associated with the risk for ESCC, suggesting an important etiology clue to the early progression of ESCC in the Huaian population of China.
PMCID: PMC3468122  PMID: 22853296
15.  Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion 
Ethanol and its metabolite, acetaldehyde, are the definite carcinogens for esophageal squamous cell carcinoma (ESCC), and reduced catalytic activity of aldehyde dehydrogenase 2 (ALDH2), which detoxifies acetaldehyde, increases the risk for ESCC. However, it remains unknown whether the ALDH2 genotype influences the level of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. In the present study, we administered ethanol orally or intraperitoneally to Aldh2-knockout and control mice, and we quantified the level of acetaldehyde-derived DNA damage, especially N2-ethylidene-2’-deoxyguanosine (N2-ethylidene-dG), in the esophagus. In the model of oral ethanol administration, the esophageal N2-ethylidene-dG level was significantly higher in Aldh2-knockout mice compared with control mice. Similarly, in the model of intraperitoneal ethanol administration, in which the esophagus is not exposed directly to the alcohol solution, the esophageal N2-ethylidene-dG level was also elevated in Aldh2-knockout mice. This result indicates that circulating ethanol-derived acetaldehyde causes esophageal DNA damage, and that the extent of damage is influenced by knockout of Aldh2. Taken together, our findings strongly suggest the importance of acetaldehyde-derived DNA damage which is induced in the esophagus of individuals with ALDH2 gene impairment. This provides a physiological basis for understanding alcohol-related esophageal carcinogenesis.
PMCID: PMC4065408  PMID: 24959382
Carcinogenesis; esophageal squamous cell carcinoma; acetaldehyde; acetaldehyde-derived DNA damage; DNA adduct
16.  Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies 
PLoS ONE  2012;7(3):e32711.
Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC).
Methodology/Principal Findings
We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure.
Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies.
PMCID: PMC3291619  PMID: 22396792
17.  Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study 
BMC Gastroenterology  2009;9:37.
Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC.
One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression.
In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 – 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 – 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 – 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 – 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 – 0.47, p for multiplicative interaction 0.008)
H. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus.
PMCID: PMC2693118  PMID: 19463183
18.  Candidate Gene Association Study of Esophageal Squamous Cell Carcinoma in a High-Risk Region in Iran 
Cancer research  2009;69(20):7994-8000.
A region with a high risk for esophageal squamous cell carcinoma (ESCC) in northeast of Iran was identified more than three decades ago. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. Polymorphisms of several genes have been associated with susceptibility to esophageal cancer in various populations, but these have not been studied in Iran. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes which previously have been suggested to be associated with an increased risk of ESCC. We genotyped a primary set of samples from 451 Turkmen (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these SNPs were then studied in a validation set of 1668 cases and controls (Turkmen and non-Turkmen) under dominant and recessive models. In the joint sample set, five variants, from five different genes, showed significant associations with ESCC at the P = 0.05 level. For one variant, in ADH1B, the association was strong and was present in both Turkmen and non-Turkmen. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC under a recessive model (OR = 0.41, 95%, CI = 0.19 to 0.49; P = 4×10−4). For four additional variants, an association was present in the Turkmen subgroup, but the statistical significance of these was less compelling than for ADH1B. Two variants showed deleterious effects and two were protective. The G allele of the c.870A>G variant of CCND1 gene was associated with a 1.5-fold increased risk of ESCC under the recessive model (OR = 1.50, 95% CI = 1.14 to 2.16, P = 0.02) and the A allele of the rs1625895 variant of TP53 gene was associated with a 1.5-fold increased risk of ESCC under a dominant model (OR = 1.54, 95% CI = 1.21 to 4.07, P = 0.005). The C allele of the rs886205 variant of ALDH2 was associated with a decreased risk of ESCC under a recessive model (OR = 0.58, 95% CI = 0.34 to 0.87, P = 0.02) and the A allele of the rs7087131 variant of MGMT was associated with a decreased risk of ESCC under the recessive model (OR = 0.26, 95% CI = 0.05 to 0.49, P=0.01). These results confirm that genetic predisposition to ESCC plays a role in high incidence of this cancer among Turkmens who live in northeast of Iran.
PMCID: PMC3505030  PMID: 19826048
Esophageal squamous cell carcinoma; Turkmen population; ADH1B; ALDH2; MGMT; TP53; CCND1
19.  Dental Status and Associated Factors in a Dentate Adult Population in Bulgaria: A Cross-Sectional Survey 
This study aimed to determine variations in the dental status of a dentate adult population in terms of “decayed,” “missing,” and “filled” teeth in relation to several sociodemographic and behavioral factors. Quota sampling was used to draw 2531 subjects aged 20 years and over. Data were collected by means of a questionnaire and an oral examination. Multiple logistic regression analyses were performed to observe associations between “decayed,” “missing,” and “filled” teeth and the factors of interest. The mean numbers of “decayed,” “missing,” and “filled” teeth were 2.2, 6.7, and 4.9, respectively. Molar teeth were significantly more often “missing” than premolar and anterior teeth. Age, gender, education, and tooth brushing revealed most noticeable associations. Increasing age was associated with a lower chance of having “decayed” and “filled” teeth, but with a higher chance of having “missing” teeth. Females were more likely to have “missing” and “filled” teeth. Higher education was associated with a lower chance of having “missing” teeth. More frequent tooth brushing was associated with a lower chance of having “decayed” and “missing” teeth, but with a higher chance of having “filled” teeth. These risk indicators should be considered in prevention program planning if reduction of tooth loss is to be achieved.
PMCID: PMC3359670  PMID: 22654908
20.  Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma 
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of squamous cell carcinomas. Common genetic lesions in ESCC include p53 mutations and EGFR overexpression, both of which have been implicated in negative regulation of Notch signaling. In addition, cyclin D1 is overexpressed in ESCC and can be activated via EGFR, Notch and Wnt signaling. To elucidate how these genetic lesions may interact during the development and progression of ESCC, we tested a panel of genetically engineered human esophageal cells (keratinocytes) in organotypic 3D culture (OTC), a form of human tissue engineering. Notch signaling was suppressed in culture and mice by dominant negative Mastermind-like1 (DNMAML1), a genetic pan-Notch inhibitor. DNMAML1 mice were subjected to 4-Nitroquinoline 1-oxide-induced oral-esophageal carcinogenesis. Highly invasive characteristics of primary human ESCC were recapitulated in OTC as well as DNMAML1 mice. In OTC, cyclin D1 overexpression induced squamous hyperplasia. Concurrent EGFR overexpression and mutant p53 resulted in transformation and invasive growth. Interestingly, cell proliferation appeared to be regulated differentially between those committed to squamous-cell differentiation and those invading into the stroma. Invasive cells exhibited Notch-independent activation of cyclin D1 and Wnt signaling. Within the oral-esophageal squamous epithelia, Notch signaling regulated squamous-cell differentiation to maintain epithelial integrity, and thus may act as a tumor suppressor by preventing the development of a tumor-promoting inflammatory microenvironment.
PMCID: PMC3410579  PMID: 22860235
Esophageal squamous cell carcinoma; organotypic 3D culture; EGFR; P53; cyclin D1; Wnt; Notch; squamous-cell differentiation; invasion; 4-Nitroquinoline 1-oxide
21.  The Effect of Intensive Oral Hygiene Care on Gingivitis and Periodontal Destruction in Type 2 Diabetic Patients 
Yonsei Medical Journal  2009;50(4):529-536.
This study aimed to investigate the effects of oral hygiene care by oral professionals on periodontal health in type 2 diabetes mellitus patients.
Materials and Methods
Diabetic participants were recruited at a university hospital and matched at a 1:1 ratio by age and gender, and randomly allocated into intervention (40 people) and control groups (35 people). Tooth brushing instruction, oral health education, and supra-gingival scaling were implemented in all patients at baseline. This program was repeatedly conducted in intervention patients every month for 6 months, and twice at baseline and the sixth month in the control. Oral health was measured by decayed, missing, and filled teeth (DMFT), plaque index, calculus index, bleeding index, patient hygiene performance (PHP) index, tooth mobility, Russel's periodontal index, and community periodontal index (CPI). Diabetes-related factors, oral and general health behaviors, and sociodemographic factors were interviewed as other confounding factors. An analysis of covariance (ANCOVA) was used with SPSS for Windows 14.0.
At baseline, there were no significant differences between the two groups in average of periodontal health (calculus index, bleeding index, Russel's periodontal index, CPI, and tooth mobility), diabetes-related factors (fasting blood glucose, postprandial blood glucose, and HbA1c), and in distribution of sociodemographic factors and health behaviors. In intervention group, plaque index, dental calculus index, bleeding index, and PHP index were reduced fairly and steadily from the baseline. There were significant differences in plaque index, dental calculus index, bleeding index, PHP index, and Russel's periodontal index between the two groups at sixth month after adjusted for baseline status.
Intensive oral hygiene care can persistently improve oral inflammation status and could slow periodontal deterioration.
PMCID: PMC2730616  PMID: 19718402
Dental prophylaxis; oral hygiene; periodontal diseases; type 2 diabetes mellitus
22.  Identification of galectin-7 as a potential biomarker for esophageal squamous cell carcinoma by proteomic analysis 
BMC Cancer  2010;10:290.
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. Early diagnosis is critical for guiding the therapeutic management of ESCC. It is imperative to find more effective biomarkers of ESCC.
To identify novel biomarkers for esophageal squamous cell carcinoma (ESCC), specimens from 10 patients with ESCC were subjected to a comparative proteomic analysis. The proteomic patterns of ESCC samples and normal esophageal epithelial tissues (NEETs) were compared using two-dimensional gel electrophoresis. And differentially expressed proteins were identified using MALDI-TOF-MS/MS. For further identification of protein in selected spot, western blotting and immunohistochemistry were employed.
Twelve proteins were up-regulated and fifteen proteins were down-regulated in the ESCC samples compared with the NEET samples. Up-regulation of galectin-7 was further confirmed by western blotting and immunohistochemistry. Furthermore, immunohistochemical staining of galectin-7 was performed on a tissue microarray containing ESCC samples (n = 50) and NEET samples (n = 10). The expression levels of galectin-7 were markedly higher in the ESCC samples than in the NEET samples (P = 0.012). In addition, tissue microarray analysis also showed that the expression level of galectin-7 was related to the differentiation of ESCC.
The present proteomics analysis revealed that galectin-7 was highly expressed in ESCC tissues. The alteration in the expression of galectin-7 was confirmed using a tissue microarray. These findings suggest that galectin-7 could be used as a potential biomarker for ESCC.
PMCID: PMC3087317  PMID: 20546628
23.  Comparison of prevalence, viral load, physical status and expression of human papillomavirus-16, -18 and -58 in esophageal and cervical cancer: a case-control study 
BMC Cancer  2010;10:650.
Human papillomavirus (HPV) infection is a major risk factor for the development of nearly all cases of cervical cancer worldwide. The presence of HPV DNA in cases of esophageal squamous-cell carcinoma (ESCC) has been reported repeatedly from Shantou, China, and other regions with a high incidence of esophageal carcinoma (EC). However, unlike in cervical squamous-cell carcinoma (CSCC), in ESCC, the characteristics of HPV are unclear. Thus, the role of high-risk HPV types in the carcinogenesis of ESCC remains uncertain.
Seventy cases of ESCC with 60 controls and 39 cases of CSCC with 54 controls collected from patients in Shantou region in China were compared for the distributions of HPV-16, -18 and -58; viral load; and viral integration using real-time PCR assay and HPV-16 expression using immunostaining.
The detection rates and viral loads of HR-HPV infection were significantly lower in ESCC than in CSCC (50.0% vs. 79.48%, P = 0.005; 2.55 ± 3.19 vs. 361.29 ± 441.75, P = 0.002, respectively). The combined integration level of HPV-16, -18 and -58 was slightly lower in ESCC than in CSCC (P = 0.022). HPV-16 expression was detected in 59.26% of ESCC tissue and significantly associated with tumour grade (P = 0.027).
High levels of HR-HPV expression and integration may be an indicator of the risk of ESCC, at least for patients in the Shantou region of China. However, a relatively low HPV copy number and infection rate in ESCC is unlikely to play an essential a role in the carcinogenesis of ESCC as in cervical cancer. Factors other than HR-HPV infection may contribute to the carcinogenesis of ESCC.
PMCID: PMC3001448  PMID: 21108842
24.  Down-regulation of microRNA 10a expression in esophageal squamous cell carcinoma cells 
Oncology Letters  2010;1(3):527-531.
This study identified significantly down-regulated microRNAs (miRs) specific for esophageal squamous cell carcinoma (ESCC) cells. Total RNA was extracted from ESCC cell lines (OE21 and TE10) and a non-malignant human esophageal squamous cell line (Het1A), and subjected to microarray analysis. Expression levels of miRs that showed significant down-regulation in ESCC cells compared to Het1A cells based on the comprehensive analysis were analyzed by quantitative reverse transcription polymerase chain reaction. Among the significantly down-regulated miRs, miR-10a expression levels in the five ESCC cell lines examined were significantly lower than in Het1A and the esophageal adenocarcinoma cells. Since miR-10a is a specific miR in ESCC, its clinical relevance was examined. Using ESCC tumor samples and non-cancerous tissue obtained endoscopically, the involvement of miR-10a in the clinicopathological findings was examined. MiR-10a expression was comparably down-regulated in the tumors of high-grade intraepithelial neoplasm and non-invasive ESCC, while the expression levels were elevated in the invasive ESCC tumors. Treatment with a demethylating agent, 5-aza-2′-deoxycytidine, restored miR-10a expression in OE21 cells. Only a modest additive or synergistic effect was observed in the presence of a histone deacetylase inhibitor, trichostatin A. These results imply that miR-10a may be differentially expressed in ESCC cells and may be involved in ESCC development and progression. The unique epigenetic regulation of miR-10a expression can be mediated via hypermethylation of the CpG islands proximal to its gene locus, at least in certain ESCC cells.
PMCID: PMC3436400  PMID: 22966337
microRNA; microRNA 10a; esophageal squamous cell carcinoma; DNA methylation
25.  Increased serum cell-free DNA levels in relation to inflammation are predictive of distant metastasis of esophageal squamous cell carcinoma 
Distant metastasis hinders a favorable outcome for patients with esophageal squamous cell carcinoma (ESCC) by limiting the surgical cure. The levels of cell-free DNA (cfDNA) in the blood have served as a predictor for metastasis and recurrence in distant organs in liver cancer. Thus, this study tested the clinical efficacy of serum cfDNA levels as a predictive marker for distant metastasis of ESCC. We investigated cfDNA levels in a cohort of 101 ESCC patients and 46 age- and gender-matched control patients with benign disease. We found that serum cfDNA levels were significantly higher in the ESCC patients than in the control patients (P=0.034). In the ESCC patients, serum cfDNA levels were positively associated with tumor size and cytokeratin 19 fragment (CYFRA 21-1) expression (r=0.416 and r=0.573, respectively). An increase in cfDNA levels was also associated with host inflammation status including C-reactive protein levels and neutrophil and monocyte numbers in the peripheral blood. Serum cfDNA levels tended to be higher in advanced tumors when compared to early stage tumors. We found that serum cfDNA levels were significantly higher in ESCC patients with distant metastasis than in those without (P=0.011). Logistic regression analysis showed that serum cfDNA levels represented only one independent risk factor for distant metastasis among the five factors tested including gender, age, cfDNA levels, CYFRA 21-1 and squamous cell carcinoma antigen levels (P=0.0414). These results suggest that increased serum cfDNA levels may serve as a useful predictor for distant metastasis of ESCC.
PMCID: PMC3490399  PMID: 23136599
cell-free DNA; esophageal squamous cell carcinoma; real-time PCR; prognosis; serum

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