The role of dietary carotenoids in preventing the development of esophageal squamous cell carcinoma.

This study was to evaluate the associations of dietary intake of total and specific phytosterols and risk of esophageal squamous cell carcinoma (ESCC) and to explore their joint effects with PLCE1 rs2274223 polymorphisms. A population-based case-control study was conducted in a Chinese rural population and 856 eligible incident ESCC cases and 856 controls were included. A validated food frequency questionnaire was used to collect dietary consumption and PLCE1 rs2274223 polymorphisms were genotyped. Unadjusted and adjusted odds ratios (ORs) with 95% confidence interval (CI) were assessed via logistic regression model. When comparing the highest with lowest intake quartiles, β-sitosterol, campesterol, stigmasterol, β-sitostanol, campestanol, and total phytosterols were all associated with a decreased risk of ESCC, with adjusted ORs being 0.32 (95% CI 0.20-0.48), 0.18 (95% CI 0.11-0.27), 0.45 (95% CI 0.29-0.70), 0.13 (95% CI 0.08-0.20), 0.14 (95% CI 0.09-0.22) and 0.28 (95% CI 0.18-0.43), respectively. An exposure-response relationship was also observed for both total and five specific phytosterols (all P for trend < 0.001). In comparison to rs2274223 AA genotype, both GA genotype (OR: 1.47, 95% CI 1.16-1.85) and GG genotype (OR: 2.13, 95% CI 1.20-3.84) were associated with an increased risk of ESCC. However, no interaction was observed between total/specific phytosterols intake and rs2274223 polymorphisms. Higher dietary intake of total and five specific phytosterols was associated with a lower risk of ESCC, and the risk of ESCC increased with the increment of rs2274223 G allele. The negative association between phytosterols and ESCC risk was not modified by rs2274223 polymorphisms. Foods or supplements rich in phytosterols are a promising source for chemoprevention of ESCC, and still, clinical trials will be required in any specific case.

Erratum: salt tea consumption and esophageal cancer: a possible role of alkaline beverages in esophageal carcinogenesis.

Dietary flavonoid intake and risk of esophageal squamous cell carcinoma: A population-based case-control study

The association of nucleotide excision repair (NER) gene polymorphisms with esophageal squamous cell carcinoma (ESCC) is inconclusive. The aim of the current study was to assess the association of repair gene xeroderma pigmentosum A (XPA) (rs-1800975) and xeroderma pigmentosum C (XPC) (rs-2228000) polymorphisms with ESCC risk as well as modifying effects of environmental factors. The genotyping was done in 450 confirmed ESCC cases and equal number of individually matched controls by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and direct sequencing methods. Conditional logistic regression models were used to assess the genotypic associations and interactions. A high ESCC risk was found in subjects who carried the homozygous minor allele of XPA (odds ratio (OR) = 3.57; 95% confidence interval (CI) = 1.76-7.23), and the risk was higher when analysis was limited to participants who were ever smokers (OR = 4.22; 95% CI = 2.01-8.88), lived in adobe houses (OR = 8.42; 95% CI = 3.74-18.95), consumed large volumes of salt tea (OR = 7.42; 95% CI = 3.30-16.69), or had a positive family history of cancer (FHC) (OR = 9.47; 95% CI = 4.67-19.20). In case of XPC, a homozygous minor allele also showed strong association with ESCC risk (OR = 4.43; 95% CI = 2.41-8.16). We again observed a very strong effect of the above environmental factors in elevating the risk of ESCC. Further, the variant genotypes of both genes in combination showed an increased risk towards ESCC (OR = 7.01; 95% CI = 3.14-15.64) and such association was synergistically significant. Salt tea consumption showed an interaction with genotypes of XPA and XPC. However, an interaction with FHC was significant in the case of XPA genotype only. XPA and XPC genotypes are associated with an increased risk of ESCC, and such association was reasonably modulated by different exposures.

Alcohol Consumption and the Risks of Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus

To further examine the association between oral hygiene and esophageal squamous cell carcinoma (ESCC) risk and the effect modification of other exposures, we conducted a population-based case-control study between 2010 and 2012 in Taixing, China, a high-risk area for ESCC. Cases were primarily recruited from endoscopy units at local hospitals, supplemented by linkage to the local Cancer Registry. Control subjects were frequency matched to cases by sex and age (5-year groups) and were randomly selected from the Taixing Population Registry. For the current analysis, data from 616 histopathologically confirmed cases and 770 controls with complete information on oral hygiene were analyzed. Unconditional logistic regression models, including oral hygiene indicators and potential behavioral confounders, were used to derive odds ratios (ORs) and 95% confidence intervals (CIs). Tooth loss was only marginally significantly associated with ESCC risk (yes vs. no, OR = 1.29, 95% CI 0.94-1.74). However, the excess risk increased with increasing numbers of lost teeth (more than 6 teeth lost vs. none, OR = 1.48, 95% CI 1.04-2.11). Tooth brushing once or less per day, compared with tooth brushing twice or more per day, was associated with a 1.81-fold increased risk of ESCC. In the stratification analyses, the increased risks associated with these indicators of oral health were more pronounced in older subjects (age ≥ 70 years), women, non-smokers, and non-drinkers. Further studies are warranted to verify these findings and to explore the underlying mechanisms, e.g., changed oral microbiota, associated with poor oral hygiene.

Objectives: Both iron overload and iron deficiency cause oxidative stress and DNA damage, which increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. In animal models, iron overload causes forestomach tumors, and in epidemiologic studies, high heme iron intake is associated with some upper GI cancers. Hemochromatosis, which results in excessive iron absorption in the GI tract, is also associated with GI cancer. The mechanism of increased cancer risk may involve the impairment of iron-dependent metabolic functions related to genome protection and maintenance. Genetic variants of genes with iron-dependent metabolic functions may confer differential GI cancer risk. Therefore, we comprehensively examined the genetic variants of these genes and risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a high-risk population in China. Methods: We genotyped 249 tag single nucleotide polymorphisms (SNPs) in 23 genes with known iron-dependent metabolic function in 1027 ESCC cases and 752 GCA cases plus 1452 controls from two epidemiologic studies in a high-risk region in China. For all genes as a single pathway and each gene individually, we calculated summary p-values using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: In pathway-based tests, the iron pathway was not associated with either ESCC (p=0.320) or GCA (p=0.550). However, in gene-based tests, HMOX2 (heme oxygenase 2, p=0.018) and BMP2 (bone morphogenetic protein 2, p=0.032) were associated with ESCC risk, and IREB2 (iron-responsive element binding protein 2, p=0.033) was associated with GCA risk. In SNP-based tests, RS235756 (OR=0.78, CI=0.66-0.91) and RS910141 (OR=0.76, CI=0.63-0.93) tagged to BMP2 (linkage disequilibrium of pairwise r2=0.55) were associated with ESCC risk. RS6500609 (OR=1.30, CI=1.08-1.57) tagged to HMOX2 was also associated with ESCC risk. RS12910090 (OR=0.83, CI=0.72-0.94) and RS2568500 (OR=0.83, CI=0.73-0.95) tagged to IREB2 (r2=0.90) were associated with GCA risk. RS11630228 (OR=1.21, CI=1.06-1.38) also tagged to IREB2 (r2&amp;lt;0.38 with two previous SNPs) was associated with GCA risk. Conclusions: The potential link between iron status and differential UGI cancer risk may involve the impairment of iron-dependent metabolic functions, which leads to oxidative stress and DNA damage. The association of SNPs in HMOX2 and BMP2 with ESCC risk and IREB2 with GCA risk suggests that genetic variants of genes with iron-dependent metabolic functions may differentially confer risk of upper GI cancer. Further research is warranted to replicate these findings and elucidate the functional effects of the SNPs in the context of upper GI carcinogenesis to better understand the role of iron overload or iron deficiency in cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2632. doi:1538-7445.AM2012-2632

BackgroundFamily history (FH) by different relative types and risk of upper gastrointestinal (UGI) cancers has been only rarely reported; the data on UGI cancer survival are sparse.Methods600 esophageal squamous cell carcinoma (ESCC) cases, 598 gastric cardia adenocarcinoma cases, and 316 gastric non-cardia adenocarcinoma cases, and 1514 age-, gender-, and neighborhood-matched controls were asked for FH in first degree relatives and non-blood relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regressions, and hazard ratios (HRs) from Cox proportional hazard regressions were estimated.ResultsIncreased ESCC risk was associated with FH of any cancer (OR = 1.72, 95% CI = 1.39–2.12), FH of any UGI cancer (OR = 2.28, 95%CI = 1.77–2.95) and FH of esophageal cancer (OR = 2.84, 95%CI = 2.09–3.86), but not FH of non-UGI cancer. Individuals with two or more affected first-degree relatives had 10-fold increased ESCC risk. FH of gastric cardia cancer was associated with an increased risk of all three cancers. Cancer in non-blood relatives was not associated with risk of any UGI cancer. FH of UGI cancer was associated with a poorer survival rate among younger ESCC cases (HR = 1.82, 95%CI = 1.01–3.29).ConclusionThese data provide strong evidence that shared susceptibility is involved in esophageal carcinogenesis and also suggest a role in prognosis.

Objectives: Observational studies and intervention trials suggest that selenium has potential cancer prevention properties. We previously found that selenium supplementation reduces cancer mortality, particularly gastric cancer mortality, in a high-risk region in China, and that low serum selenium concentration is associated with increased risks of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). In humans, selenium may exert chemopreventive actions through the 25 known selenoproteins, which contain residues of selenocysteine, the 21st amino acid. Therefore, genetic variants in selenoprotein genes may influence susceptibility to ESCC and GCA, yet no previous studies have comprehensively investigated these potential associations. Thus, we examined the association between genetic variants in selenoprotein and selenium metabolism genes and risks of ESCC and GCA. Methods: We included 1027 ESCC and 753 GCA cases plus 1452 controls from two epidemiologic studies in the high-risk region in China. We genotyped 272 tag single nucleotide polymorphisms (SNPs) in all 25 known selenoprotein genes and 4 selenium metabolism genes. For each gene, we calculated a standardized summary p-value using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: In gene-based tests, the selenoprotein gene SELS (selenoprotein S) was associated with ESCC risk (p=0.00070); TXNRD2 (thioredoxin reductase 2) showed borderline non-significant associations with both ESCC (p=0.063) and GCA (p=0.051). In SNP-based tests for these two genes, rs8029790 (tagged to SELS in the upstream noncoding region) was associated with a 1.30-fold increased risk of ESCC (CI=1.14, 1.47; p=0.000052), whereas rs2073750 (tagged to intron in TXNRD2) was associated with risks of both ESCC (OR=0.84, CI=0.74, 0.94; p=0.0029) and GCA (OR=0.82, CI=0.72, 0.93; p=0.0026). Conclusions: The potential anticarcinogenic properties of selenium may be due to its presence as the amino acid selenocysteine in human selenoproteins. The association of SNPs in selenoprotein genes SELS and TXNRD2 with ESCC and GCA risk suggests that selenium and these selenoproteins may play an important role in cancer development. Our findings warrant further research on elucidating the functional effects of these SNPs on selenoproteins in the context of upper gastrointestinal (UGI) carcinogenesis so that we can better understand the role of selenium supplementation in cancer prevention. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A59.

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84-3.14), 1.36 (1.03-1.79), 1.01 (0.76-1.35), and 1.37 (1.03-1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

Previous results regarding the associations between esophageal squamous-cell carcinoma (ESCC) risk and smoking/alcohol drinking in high-risk areas are inconsistent. We performed a large population-based case-control study from 2010 to 2013 in a high-incidence area of China, and enrolled 1353 ESCC cases and 1961 controls. Data regarding smoking and alcohol drinking were collected via face-to-face interviews using a structured questionnaire. Odd ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. After adjusting for alcohol drinking and other potential confounders, male heavy smokers (i.e., those who started smoked more than 20 cigarettes per day or 40 pack-years, or started smoking early), showed a moderately increased risk for ESCC; however, current smoking was not associated with an increased risk. Alcohol drinking among males significantly increased the risk for ESCC (OR = 2.20, 95%CI:1.79~2.70). We observed increasing excess ESCC risks with decreasing age at behavior initiation as well as with increasing duration and intensity of alcohol intake, which were particularly evident among current smokers. In contrast, neither smoking nor alcohol drinking was not associated with ESCC risk among females. In conclusion, alcohol drinking shows a monotonic dose-response relationship with ESCC risk among men, and this relationship is particularly evident among smokers.

BackgroundAlthough 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.MethodsIn 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.ResultsESCC 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.ConclusionThis 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.

BackgroundContinuous 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.MethodsA 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.ResultsConsuming 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).ConclusionOur 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.

The genetic alterations leading to esophageal squamous cell carcinoma (ESCC) are gradually being discovered. A wide variety of genes have been associated with ESCC development as well as tumor progression. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine; it promotes tumor growth and metastasis in later stages of of cancer development. Variations in the DNA sequence in the TGF-beta1 gene may lead to altered TGF-beta1 production and/or activity, and so this can modulate an individual's susceptibility to ESCC. To test this hypothesis, we investigated the association of the TGF-beta1 gene -509 C/T and 869 T/C (Leu10Pro) polymorphisms and their haplotypes with the risk of ESCC. 247 patients with ESCC and 260 age- and sex-matched controls were studied using a polymerase chain reaction-restriction fragment length polymorphism. There were significant differences in the genotype and allele distribution of 869 T/C polymorphism of the TGF-beta1 gene among cases and controls. The 869 TC and CC genotypes were associated with a significantly increased risk of ESCC as compared with the 869 TT genotypes [odds ratio (OR) = 1.882, 95% confidence interval (CI) 1.212-2.923, P = 0.005 and OR = 2.099, 95% CI 1.288-3.421, P = 0.003, respectively]. Consistent with the results of the genotyping analyses, the -509 T/869 C haplotype was associated with a significantly increased risk of ESCC as compared with the -509 C/869 T haplotype (OR = 1.463; 95% CI 1.120-1.912; P = 0.005). This study shows for the first time that TGF-beta1 gene 869 T/C polymorphism may contribute to a genetic risk factor for ESCC in a Chinese population.

Studies have persistently associated esophageal squamous cell carcinoma (ESCC) risk with low socioeconomic status (SES), but this association is unexplored in Kashmir, an area with a high incidence of ESCC in the northernmost part of India. We carried out a case-control study to assess the association of multiple indicators of SES and ESCC risk in the Kashmir valley. A total number of 703 histologically confirmed ESCC cases and 1664 controls matched to the cases for age, sex, and district of residence were recruited from October 2008 to January 2012. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. Composite wealth scores were constructed based on the ownership of several appliances using multiple correspondence analyses. Higher education, living in a kiln brick or concrete house, use of liquefied petroleum gas and electricity for cooking, and higher wealth scores all showed an inverse association with ESCC risk. Compared to farmers, individuals who had government jobs or worked in the business sector were at lower risk of ESCC, but this association disappeared in fully adjusted models. Occupational strenuous physical activity was strongly associated with ESCC risk. In summary, we found a strong relationship of low SES and ESCC in Kashmir. The findings need to be studied further to understand the mechanisms through which such SES parameters increase ESCC risk.