Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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) CONCLUSION: 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.

Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid.

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1-30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low-to-moderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk.

Carcinogenetic impact of alcohol intake on squamous cell carcinoma risk of the oesophagus in relation to tobacco smoking.

Consumption of alcohol and tobacco, separately or jointly, can increase the risk of oesophageal squamous cell carcinoma (OSCC). It is unclear whether the amount of alcohol consumption by individual drinkers affects the joint carcinogenetic action of both agents. To demonstrate how the intensity of alcohol intake determines the risk of OSCC in relation to tobacco smoking, we conducted a multicentre case-control study. A total of 652 patients with pathology-proven OSCC, as well as 1127 gender, age, and study hospital matched controls were recruited. To identify a possible curvature in the continuous relationship between exposure and risk, we applied the generalised additive models to the collected data. Both non-drinkers who smoked tobacco and non-smokers who drank heavy alcohol (>30 g/day) were observed to have elevated cancer risks. A smoking habit-specific, non-linear increase in oesophageal cancer risk was recognised. Tobacco was found to interact with light-to-moderate alcohol (0.1-30 g/day) to increase the risk of oesophageal cancer in a supra-multiplicative way (Odds ratio (OR) ratio=5.5-5.7, p<0.05), whereas with heavy alcohol consumption in a simple multiplicative model (OR ratio=1.7-2.3, p>0.05). Weekly intake frequency had the strongest influence on the risk of neoplasm development. Alcohol consumption was responsible, respectively, for 18% and 77% of nonsmoking and smoking OSCC cases in this population. In conclusion, both light-to-moderate and heavy alcohol intake interact separately with tobacco in differently synergistic processes that can determine the development of this type of cancer.

Anatomical subsite discrepancy in relation to the impact of the consumption of alcohol, tobacco and betel quid on esophageal cancer.

The carcinogenetic impact of risk factors on esophageal cancer (EC) may differ according to the portion of the esophagus where the tumor occurs. It is unclear why more esophageal squamous cell carcinomas (SCC) developed in the middle location. We carried out a multicenter case-control study in Taiwan to assess anatomical subsite risk discrepancy for this neoplasm in regard to the consumption of alcohol, tobacco and betel quid. Four hundred forty seven incident patients with pathology-proven SCC of the esophagus (107 were upper-third [U/3-EC], 199 middle-third [M/3-EC] and 141 lower-third [L/3-EC] cases), as well as 1,022 gender, age and study hospital matched controls were analyzed by unordered polytomous logistic regression. All consumption of the three substances was related to the development of each subsite of EC, with a heterogeneously higher risk for current smokers (adjusted odds ratio (AOR) = 6.2) found in M/3-EC and for current chewers, in U/3-EC (AOR = 4.9). The joint risk of contracting lower two-third EC for drinking and smoking appeared to significantly surpass those estimated by a multiplicative interaction model. Concomitant exposure to these two agents brought the risks of EC at all three subsites up to 10- to 23.9-fold and additional tobacco-free betel quid to a 30.3- to 75.0-fold. In conclusion, tumor subsite discrepancy risk is related to prolonged exposure to tobacco and betel quid with inflorescence. Alcohol interacts with tobacco in a stronger supra-multiplicative way in the middle portion of the esophagus, probably explaining why esophageal SCC occurs more commonly at this anatomical location.

The association between microsomal epoxide hydrolase genotypes and esophageal squamous-cell-carcinoma in Taiwan: interaction between areca chewing and smoking.

One hundred and forty-five ESCC patients and 352 controls were recruited from three hospitals in Taiwan to determine the association between esophageal squamous-cell-carcinoma (ESCC) and microsomal epoxide hydrolase (mEH) genotypes at Thy113His and His139Arg. Stratified by their exposures, the His113His genotype was a significant protective factor for ESCC in areca chewers and tobacco smokers. Stratified by His113 polymorphisms, the risk of contracting ESCC for participants with His113His who chewed areca and smoked was >50% less than for those with Thy113Thy. We suggest that the mEH His113His genotype can differentiate the association between smoking, areca chewing, and ESCC.

Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males.

AIM: To investigate the association between the genetic polymorphisms of ADH2 and ALDH2, lifetime alcohol consumption and esophageal cancer risk in the Taiwanese men. METHODS: Between August 2000 and June 2003, 134 pathologically-proven esophageal squamous cell carcinoma male patients and 237 male controls were recruited from Kaohsiung Medical University Hospital and Kaohsiung Veterans General Hospital in southern Taiwan. ADH2 and ALDH2 polymorphisms were genotyped using PCR-RFLP. RESULTS: Compared to those with ADH2*2/*2, individuals with ADH2*1/*2 and ADH2*1/*1 had 2.28- and 7.14-fold, respectively, increased risk of developing esophageal cancer (95%CI = 1.11-4.68 and 2.76-18.46) after adjusting for alcohol consumption and other covariates. The significant increased risk was also noted among subjects with ALDH2*1/*2 (adjusted OR (AOR) = 5.25, 95%CI = 2.47-11.19), when compared to those with ALDH2*1/*1. The increased risk of esophageal cancer was made greater, when subjects carried both ADH2*1/*1 and ALDH2*1/*2, compared to those with ADH2*1/*2 or ADH2*2/*2 and ALDH2*1/*1 (AOR = 36.79, 95%CI = 9.36-144.65). Furthermore, we found a multiplicative effect of lifetime alcoholic consumption and genotypes (ADH2 and ALDH2) on esophageal cancer risk. CONCLUSION: Our findings suggest that polymorphisms of ADH2 and ALDH2 can modify the influence of alcoholic consumption on esophageal cancer risk.

Helicobacter pylori infection: a protective factor for esophageal squamous cell carcinoma in a Taiwanese population.

AIM: Many researchers have reported the inverse relationship between Helicobacter pylori (H. pylori) infection and esophageal adenocarcinoma risk, but very few studies have examined the association between H. pylori infection and the development of esophageal squamous-cell carcinoma (ESCC). Therefore, the aim of this study is to evaluate the relationship between H. pylori infection and ESCC risk. METHOD: Subjects were cancer cases, pathologically proven to have ESCC, in two large medical centers in Kaohsiung metropolitan of southern Taiwan between August 2000 and May 2003. Controls were from the healthy subjects who lived in Kaohsiung metropolitan and voluntarily participated in one large multiyear of gene-environmental study. In total, 127 cases (116 males and 11 females) and 171 controls (161 males and 10 females) were recruited in the same period of time for interviews. H. pylori seropositivity was determined by an enzyme-linked immunosorbant assay measuring IgG. RESULTS: A total of 28 (22.1%) and 74 (43.3%) out of 127 cases and 171 controls, respectively, had positive H. pylori infection. After adjusting for other covariates, subjects with positive H. pylori infections had a significantly reduced risk (adjusted odds ratio (AOR) = 0.51; 95% CI = 0.27-0.96; p= 0.037) of developing ESCC than those without. This result was even more pronounced in the groups of younger subjects, nonsmokers, or nondrinkers. In addition, among the 117 cancer patients who provided information about site of cancer lesion, the present study found that subjects with cancer lesions in the lower third of the esophagus had significantly fewer positive H. pylori infections (AOR = 0.34; 95% CI = 0.14-0.80; p= 0.013) than controls. CONCLUSION: Our findings suggest that H. pylori infection may protect against the development of ESCC. Additional studies are needed to confirm these findings.

Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan.

A multicenter case-control study was conducted in northern and southern Taiwan to clarify the independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer. A total of 513 patients with newly diagnosed and histopathologically confirmed squamous cell carcinoma of the esophagus and 818 gender, age and study hospital-matched controls were included. We found a significant dose-response relationship between the duration and intensity of consumption of the 3 substances and the development of this neoplasm in this site. Although the amount of alcohol consumed had a stronger effect on the risk of esophageal cancer than the number of years it was consumed, however, the number of years one smoked had a stronger effect on the risk than the amount of cigarettes consumed. The strongest risk factor of esophageal cancer was alcohol intake, with highest risk (OR = 13.9) being for those who consumed more than 900 g/day-year. Combined exposure to any 2 of 3 substances brought the risks up to 8.8-19.7 fold and, to all 3 substances, to 41.2-fold. A multiplicative interaction effect for alcohol drinkers who smoked on cancer risk was detected, whereas an additive interaction effect was found among drinkers who chewed. The combined effect of all 3 substances accounted for 83.7% of the attributable fraction of contracting esophageal cancer in this population. In conclusion, these results suggest that the intensity and the length of time alcohol and tobacco are used play different roles in the etiology of esophageal cancer. Alcohol separately interacts with tobacco and betel quid in a differently synergistic way in determining the development of this site of cancer.

Association between p21 codon 31 polymorphism and esophageal cancer risk in a Taiwanese population.

P21, which regulates the cell growth cycle, is crucial for normal growth and differentiation. One polymorphism in the p21 codon 31 produces variant proteins with an amino acid change (serine (ser) or arginine (arg)). Although several epidemiologic studies have examined the effect of this polymorphism on cancer risk, the findings remain inconclusive, which has motivated us to evaluate the relationship between p21 codon 31 polymorphism and esophageal cancer risk. In this study, 128 cases of esophageal squamous cell carcinoma and 178 control cases from two hospitals in southern Taiwan were genotyped. Frequencies of arg/arg, arg/ser and ser/ser were 23 (18.0%), 62 (48.4%) and 43 (33.6%) in carcinoma cases and 51 (28.6%), 84 (47.2%) and 43 (24.2%) in control cases, respectively. After factoring out other potential contributing factors, patients with ser/ser or arg/ser were 2.17 times more at risk (95% CI=1.03-4.56) for developing esophageal cancer than those with arg/arg. Males (n=274) were found to have a slightly stronger association (adjusted OR=2.45; 95% CI=1.03-5.80). Although the sample size is relatively small, these findings suggest that a codon 31 polymorphism in p21 may be associated with the development of esophageal cancer.

SULT1A1 polymorphism and esophageal cancer in males.

Sulfotransferase (SULT) 1A1 detoxifies and bioactivates a broad spectrum of substrates including xenobiotics. It has been suggested that the SULT1A1 his (histidine) allele, which is caused by a his for arg (arginine) substitution due to a G-->A transition at codon 213, carries a significantly higher risk for women to develop breast cancer. We investigated the association between the SULT1A1 arg/his genotype and esophageal cancer in men, 187 cases of esophageal squamous cell carcinoma and 308 controls from 3 medical centers in Taiwan. Cigarette smoking, areca chewing and alcohol consumption were the major risks for developing esophageal cancer. The frequencies of arg/his in cases and controls were 27.8% (52/187) and 11.0% (34/308), respectively (p < 0.0001). No subjects carried his/his. After adjusting for substance use and other covariates, individuals with arg/his had a 3.53-fold higher risk (95% CI = 2.12-5.87) of developing esophageal cancer than those with arg/arg. Unexpectedly, this positive association was found to be even stronger (adjusted OR = 4.04-4.80) among non-smokers, non-drinkers or non-chewers. Our findings suggest that the SULT1A1 his(213) allele is important in the development of esophageal cancer in men.