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1.  Global Changes in Gene Expression of Barrett's Esophagus Compared to Normal Squamous Esophagus and Gastric Cardia Tissues 
PLoS ONE  2014;9(4):e93219.
Background
Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE.
Design
We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients.
Results
Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-β and Notch.
Conclusion
Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.
doi:10.1371/journal.pone.0093219
PMCID: PMC3979678  PMID: 24714516
2.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999
3.  Genetic Variants in Epidermal Growth Factor Receptor Pathway Genes and Risk of Esophageal Squamous Cell Carcinoma and Gastric Cancer in a Chinese Population 
PLoS ONE  2013;8(7):e68999.
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1371/journal.pone.0068999
PMCID: PMC3715462  PMID: 23874846
4.  Comparison of Global Gene Expression of Gastric Cardia and Noncardia Cancers from a High-Risk Population in China 
PLoS ONE  2013;8(5):e63826.
Objective
To profile RNA expression in gastric cancer by anatomic subsites as an initial step in identifying molecular subtypes and providing targets for early detection and therapy.
Methods
We performed transcriptome analysis using the Affymetrix GeneChip U133A in gastric cardia adenocarcinomas (n = 62) and gastric noncardia adenocarcinomas (n = 72) and their matched normal tissues from patients in Shanxi Province, and validated selected dysregulated genes with additional RNA studies. Expression of dysregulated genes was also related to survival of cases.
Results
Principal Component Analysis showed that samples clustered by tumor vs. normal, anatomic location, and histopathologic features. Paired t-tests of tumor/normal tissues identified 511 genes whose expression was dysregulated (P<4.7E-07 and at least two-fold difference in magnitude) in cardia or noncardia gastric cancers, including nearly one-half (n = 239, 47%) dysregulated in both cardia and noncardia, one-fourth dysregulated in cardia only (n = 128, 25%), and about one-fourth in noncardia only (n = 144, 28%). Additional RNA studies confirmed profiling results. Expression was associated with case survival for 20 genes in cardia and 36 genes in noncardia gastric cancers.
Conclusions
The dysregulated genes identified here represent a comprehensive starting point for future efforts to understand etiologic heterogeneity, develop diagnostic biomarkers for early detection, and test molecularly-targeted therapies for gastric cancer.
doi:10.1371/journal.pone.0063826
PMCID: PMC3661768  PMID: 23717493
5.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
6.  Cigarette Smoking Increases Risk of Barrett’s Esophagus: an Analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium 
Gastroenterology  2012;142(4):744-753.
Background & Aims
Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett’s esophagus (BE). We investigated whether tobacco smoking and other factors increase risk for BE.
Methods
We analyzed data from 5 case-control studies included in the international Barrett’s and Esophageal Adenocarcinoma Consortium. We compared data from subjects with BE (n=1059) with those from subjects with gastroesophageal reflux disease (GERD controls, n=1332) and population-based controls (n=1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for BE.
Results
Subjects with BE were significantly more likely to have ever-smoked cigarettes than the population-based controls (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.04–2.67) or GERD controls (OR=1.61; 95% CI, 1.33–1.96). Increasing pack-years of smoking increased the risk for BE. There was evidence for a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (0.25–0.52).
Conclusions
Cigarette smoking is a risk factor for BE. The association strengthened with increased exposure to smoking until ~ 20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to the development of BE.
doi:10.1053/j.gastro.2011.12.049
PMCID: PMC3321098  PMID: 22245667
BEACON; esophageal cancer; population study; tobacco
7.  Non-Steroidal Anti-Inflammatory Drug Use Reduces Risk for Adenocarcinomas of the Esophagus and Esophagogastric Junction in a Pooled Analysis 
Gastroenterology  2011;142(3):442-e23.
Background & Aims
Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) has been reported to reduce risks for esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations.
Methods
We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model.
Results
Compared to non-users, individuals who have used NSAIDs had a statistically significant, reduced risk of EAC (OR=0.68; 95% CI, 0.56–0.82); they also appeared to have a reduced risk of EGJA (OR=0.84; 95% CI, 0.68–1.03). Similar reductions in risk were observed among individuals who took aspirin or non-aspirin NSAIDs. The highest levels of frequency (≥daily) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk for EAC: OR=0.56 (95% CI, 0.43–0.73; P-trend, <.001) and OR=0.63 (95% CI, 0.45–0.90; P-trend, 0.04), respectively.
Conclusions
Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, pooled analysis indicates a role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
doi:10.1053/j.gastro.2011.11.019
PMCID: PMC3488768  PMID: 22108196
BEACON; Esophageal Neoplasm; Stomach Cancer; Anti-Inflammatory Agent
8.  Risk factors for esophageal and gastric cancers in Shanxi Province, China: A case-control study 
Cancer epidemiology  2011;35(6):e91-e99.
Objective
Smoking and alcohol consumption explain little of the risk for upper-gastrointestinal (UGI) cancer in China, where over half of all cases in the world occur.
Methods
We evaluated questionnaire-based risk factors for UGI cancers in a case-control study from Shanxi Province, China, including 600 esophageal squamous cell carcinomas (ESCC), 599 gastric cardia adenocarcinomas (GCA), 316 gastric noncardia adenocarcinomas (GNCA), and 1514 age- and gender-matched controls.
Results
Ever smoking and ever use of any alcohol were not associated with risk of UGI cancer; only modest associations were observed between ESCC risk and highest cumulative smoking exposure, as well as GNCA risk and beer drinking. While several associations were noted for socioeconomic and some dietary variables with one or two UGI cancers, the strongest and most consistent relations for all three individual UGI cancers were observed for consumption of scalding hot foods (risk increased 150% to 219% for daily vs never users) and fresh vegetables and fruits (risk decreased 48% to 70% for vegetables and 46% to 68% for fruits, respectively, for high vs low quartiles).
Conclusion
This study confirms the minor role of tobacco and alcohol in UGI cancers in this region, and highlights thermal damage as a leading etiologic factor.
doi:10.1016/j.canep.2011.06.006
PMCID: PMC3215853  PMID: 21846596
smoking; alcohol; socioeconomic status; diet
9.  The importance of delivery rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett’s and Esophageal Adenocarcinoma Consortium 
Cancer epidemiology  2012;36(3):306-316.
Background
Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration.
Methods
The authors pooled data from 12 case-control studies from the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1,242 (EAC), 1,263 (EGJA) and 954 (ESCC) cases and 7,053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux.
Results
For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01).
Conclusions
Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases.
doi:10.1016/j.canep.2012.03.001
PMCID: PMC3489030  PMID: 22504051
alcohol drinking; risk model; smoking
10.  Alcohol intake and risk of esophageal adenocarcinoma: a pooled analysis from the BEACON Consortium 
Gut  2011;60(8):1029-1037.
Background and aims
Alcohol intake is a strong and well-established risk factor for esophageal squamous cell carcinoma (ESCC), but the association with esophageal adenocarcinoma (EA) or adjacent tumors of the esophagogastric junction (EGJA), remains unclear. Therefore, we determined the association of alcohol intake with ESCC, EA, and EGJA in nine case-control studies and two cohort studies of the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON).
Materials and methods
We collected information on alcohol intake, age, sex, education, body mass index, gastroesophageal reflux, and tobacco smoking from each study. Along with 10,854 controls, 1,821 EA, and 1,837 EGJA, seven studies also collected ESCC cases (n=1,016). Study-specific odds ratios (OR) and 95% confidence intervals (CI) were calculated from multivariate-adjusted logistic regression models for alcohol intake in categories compared to non-drinkers. Summary risk estimates were obtained by random effects models.
Results
We observed no increase in risk of EA or EGJA for increasing levels of any of the alcohol intake measures examined. ORs for the highest frequency category (≥7 drinks per day) were 0.97 (95% CI = 0.68-1.36) for EA and 0.77 (95% CI = 0.54-1.10) for EGJA. Suggestive findings linked moderate intake (e.g. 0.5 to <1 drinks per day) to decreased risk of EA (OR = 0.63 95% CI = 0.41-0.99) and EGJA (OR = 0.78; 95% CI = 0.62-0.99). In contrast, alcohol intake was strongly associated with increased risk of ESCC (OR for ≥7 drinks per day= 9.62, 95%CI=4.26-21.71).
Conclusions
In contrast to ESCC, higher alcohol consumption was not associated with increased risk of either EA or EGJA. The apparent inverse association observed with moderate alcohol intake should be evaluated in future prospective studies.
doi:10.1136/gut.2010.233866
PMCID: PMC3439838  PMID: 21406386
Alcohol Drinking; Esophageal Neoplasms; Stomach Neoplasms; Epidemiology
11.  Global gene expression profiling and validation in esophageal squamous cell carcinoma (ESCC) and its association with clinical phenotypes 
Purpose
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy.
Experimental Design
We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies.
Results
A total of 159 genes showed differences with extreme statistical significance (P
Conclusion
We identified an expanded panel of genes dysregulated in ESCC and confirmed previously identified differentially-expressed genes. Microarray-based gene expression results were confirmed by RT-PCR and protein expression studies. These dysregulated genes will facilitate molecular categorization of tumor subtypes and identification of their risk factors, and serve as potential targets for early detection, outcome prediction, and therapy.
doi:10.1158/1078-0432.CCR-10-2724
PMCID: PMC3086948  PMID: 21385931
esophageal squamous cell carcinoma (ESCC); Affymetrix oligomicroarray; RT-PCR; tissue microarray (TMA)
Cancer causes & control : CCC  2009;20(10):1997-2007.
Epidemiological data on green/jasmine tea and esophageal as well as gastric cancer are limited and inconclusive. In order to study the effect of jasmine tea in upper gastrointestinal (UGI) cancers, we evaluated 600 esophageal squamous cell carcinoma (ESCC), 598 gastric cardia adenocarcinoma (GCA), and 316 gastric non-cardia adenocarcinoma (GNCA) cases and 1514 age-, gender-, and neighborhood-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression adjusted for matching factors and potential confounders. Among controls, 35% of males and 8% of females reported consumption of jasmine tea; other tea consumption was rare. Consumption of jasmine tea (ever vs. never) was not associated with risk of ESCC (OR=1.15, 95% CI 0.92–1.44), GCA (OR=1.14, 95% CI 0.88–1.37), or GNCA (OR=0.85, 95% CI 0.64–1.15) in males and females combined. Among males, cumulative lifetime consumption showed a significant positive dose-response relation with ESCC risk, but not for GCA and GNCA. In exploratory analyses, occupation affected the relation between tea and ESCC such that consumption in males was associated with increased risk only in non-office workers. Overall, we found no evidence for a protective effect of tea in esophageal or gastric cancer. Further studies of the potential effects of thermal damage, tea quality, and water quality on UGI cancers are suggested.
doi:10.1007/s10552-009-9394-z
PMCID: PMC3236106  PMID: 19597950
jasmine tea; esophageal cancer; gastric cancer
Anticancer research  2011;31(3):945-952.
Background
Several studies have suggested that fascin, cytokeratin 14 and cytokeratin 4 may have significant roles as biomarkers for the progression and survival of esophageal squamous cell carcinoma (ESCC).
Methods
This study performed immunohistochemistry in tissue microarrays, profiling premalignant lesions and invasive tumors.
Results
Fascin increased across the following states as follows: normal epithelium (26%) to dysplasia (46%) to ESCC (68%), while CK4 was undetectable in ESCC (0%) compared to normal epithelium (45%) or dysplasia (41%). CK14 was elevated and invariant in expression. In regression analyses, compared to normal epithelium, higher fascin expression was associated with a 36% increased risk of dysplasia (odds ratio=1.36) and a 56% increased risk of invasive ESCC (odds ratio=1.56).
Conclusions
Expression of fascin is up-regulated in the transformation from normal epithelium, through dysplasia, into invasive carcinoma. Expression of CK4, CK14 and fascin did not correlate with patient survival. Fascin has a potential role as an early detection biomarker and CK4 as a tumor marker in ESCC.
PMCID: PMC3236111  PMID: 21498718
Background
Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose–response, and duration of cigarette smoking cessation.
Methods
We used primary data from 10 population-based case–control studies and two cohort studies from the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided.
Results
The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose–response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and ≥10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar.
Conclusions
Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.
doi:10.1093/jnci/djq289
PMCID: PMC2935475  PMID: 20716718
This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine down-regulated IL-2 by 9% (p=0.04), while celecoxib down-regulated IL-7 by 11% (p=0.006) and up-regulated IL-13 by 17% (p=0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall (OR=1.47, p=0.03) and among those with mild dysplasia at t0 (OR=2.53 p=0.001). An increase in IL-2 tertile from baseline to t10 was also non-significantly associated with worsening dysplasia for all participants (OR=1.32 p=0.098), and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR=2.0 p=0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR=2.52 p=0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, while celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10 month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect on reducing levels of IL-2.
doi:10.1158/1940-6207.CAPR-09-0269
PMCID: PMC2900463  PMID: 20587703
chemoprevention; interleukin-2; preneoplasia; gastrointestinal tract; selenium
Nature genetics  2010;42(9):764-767.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×10−9; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.649
PMCID: PMC2947317  PMID: 20729852
Background
Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma (ESCC), and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia (HGD), and who did or did not have a family history (FH) of upper gastrointestinal cancer (UGI Ca).
Methods
147 samples were evaluated, including 23 (16%) from patients with HGD and 48 (33%) from patients without DYS who heated their homes with coal, without a chimney (a “high” indoor air pollution group), and 27 (18%) from patients with HGD and 49 (33%) from patients without DYS who did not heat their homes at all (a “low” indoor air pollution group). Nearly half (64 (44%)) had a FH of UGI Ca. RNA was extracted and Quantitative-PCR analysis was performed.
Results
AhR gene expression was detectable in 85 (58%) of the samples, and was more than 9-fold higher in those with a FH of UGI Ca (median expression (IQR) -1964 (-18000, -610) versus -18000 (-18000, -1036) Wilcoxon P = 0.02). Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression, all P-values ≥0.1).
Conclusion
AhR expression was higher in patients with a FH of UGI Ca. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer.
doi:10.1158/1055-9965.EPI-08-1098
PMCID: PMC2796959  PMID: 19690180
Gastrointestinal tract cancer; Esophagus; Aryl hydrocarbon receptor; family history of cancer; gene expression; polycyclic aromatic hydrocarbons
Cancer research  2009;69(14):5908-5917.
Genomic instability plays an important role in most human cancers. To characterize genomic instability in esophageal squamous cell carcinoma (ESCC), we examined loss of heterozygosity (LOH), copy number (CN) loss, CN gain, and gene expression using the Affymetrix GeneChip Human Mapping 500K (n=30 cases) and Human U133A (n=17 cases) arrays in ESCC cases from a high-risk region of China. We found that genomic instability measures varied widely among cases and separated them into two groups: a high-frequency instability group (two-thirds of all cases with one or more instability category ≥ 10%) and a low-frequency instability group (one-third of cases with instability < 10%). Genomic instability also varied widely across chromosomal arms, with the highest frequency of LOH on 9p (33% of informative single nucleotide polymorphisms (SNPs)), CN loss on 3p (33%), and CN gain on 3q (48%). Twenty-two LOH regions were identified: four on 9p, seven on 9q, four on 13q, two on 17p, and five on 17q. Three CN loss regions – 3p12.3, 4p15.1, and 9p21.3 – were detected. Twelve CN gain regions were found, including six on 3q, one on 7q, four on 8q, and one on 11q. One of the most gene-rich of these CN gain regions was 11q13.1-13.4, where 26 genes also had RNA expression data available. CN gain was significantly correlated with increased RNA expression in over 80% of these genes. Our findings demonstrate the potential utility of combining CN analysis and gene expression data to identify genes involved in esophageal carcinogenesis.
doi:10.1158/0008-5472.CAN-08-4622
PMCID: PMC2734334  PMID: 19584285
esophageal cancer; LOH; copy number alteration; 500K SNP array
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
In a previous pilot case-control study of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) and matched controls from a high-risk area in China, we identified 38 single nucleotide polymorphisms (SNPs) associated with ESCC located in or near one of 33 genes. In the present study, we attempted to replicate the results of these 38 gene-related SNPs in a new sample of 300 ESCC cases and 300 matched controls from the same study conducted in Shanxi Province, China. Among 36 evaluable SNPs, four were significant in one or more analyses, including SNPs located in EPHB1, PGLYRP2, PIK3C3, and SLC9A9, although the odds ratios (ORs) for these genotypes were modest. Associations were found with EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019), PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02), and PGLYRP2/rs959117 (OR 0.93, 95% CI, 0.86-1.01; p = 0.061) in general linear models (additive mode); and the genotype distribution differed between cases and controls for SLC9A9/rs956062 (p = 0.024). To examine these four genes in more detail, 40 HapMap-based tag SNPs from these four genes were evaluated in the same subjects, and seven additional SNPs associated with ESCC were identified. Further confirmation of these findings in other populations and other studies are needed to determine if the signals from these SNPs are indirectly associated due to linkage disequilibrium, or are directly related to biologic function and the development of ESCC.
doi:10.1002/ijc.23682
PMCID: PMC2552411  PMID: 18649358
Esophageal cancer; Replication study; SNP
BMC Cancer  2009;9:310.
Background
Cancer of the esophagus is a deadly malignancy, and development of biomarkers that predict survival is an urgent need. The apoptotic pathways have been hypothesized as important in progression of esophageal squamous cell carcinoma (ESCC). We investigated a panel of proteins that regulate apoptosis as candidate of biomarkers of prognosis in ESCC.
Methods
Tissue microarray (TMA) including 313 surgically-resected cases of ESCC specimens was built for immunohistochemical interrogation. We evaluated seven genes in the FasL-Fas apoptotic pathway - FasL, Fas, FAS-associated death domain protein (FADD), phosphorylated-FADD, and caspase 8 and 10, and the antiapoptotic protein bcl-2. We studied pathway integrity and relations to risk and clinical factors, and determined the prognostic significance of each marker.
Results
Five markers showed strong inter-marker correlations (r ≥ 0.28, p < 0.001), including FasL, Fas, FADD, and caspases 8 and 10. FasL and FADD also showed modest correlations with one or more cancer risk factors, but none of the markers was significantly associated with either tumor stage or lymph node metastasis, the only two clinical factors that predicted survival in these ESCC cases. Multivariate-adjusted proportional hazard regression models showed no association between protein expression and risk of death for any of the seven markers examined.
Conclusion
Individual biomarkers in the apoptosis pathway do not appear to predict survival of patients with ESCC.
doi:10.1186/1471-2407-9-310
PMCID: PMC2745431  PMID: 19728877
Molecular events associated with the initiation and progression of esophageal squamous cell carcinoma (ESCC) remain poorly understood, but likely hold the key to effective early detection approaches for this almost invariably fatal cancer. CDC25B and LAMC2 are two promising early detection candidates emerging from new molecular studies of ESCC. To further elucidate the role of these two genes in esophageal carcinogenesis, we performed a series of studies to: (i) confirm RNA over-expression; (ii) establish the prevalence of protein over-expression; (iii) relate protein over-expression to survival; and (iv) explore their potential as early detection biomarkers. Results of these studies indicated that CDC25B mRNA was over-expressed (≥2-fold over-expression in tumor compared to normal) in 64% of the 73 ESCC cases evaluated, while LAMC2 mRNA was over-expressed in 89% of cases. CDC25B protein expression was categorized as positive in 59% (144/243) of ESCC cases on a tumor tissue microarray, and non-negative LAMC2 patterns of protein expression were observed in 82% (225/275) of cases. Multivariate-adjusted proportional hazard regression models showed no association between CDC25B protein expression score and risk of death (Hazard Ratio [HR] for each unit increase in expression score = 1.00, P=0.90), however, several of the LAMC2 protein expression patterns strongly predicted survival. Using the cytoplasmic pattern as the reference (the pattern with the lowest mortality), cases with a diffuse pattern had a 254% increased risk of death (HR=3.52, P=0.007), cases with no LAMC2 expression had a 169% increased risk of death (HR=2.69, P=0.009), and cases with a peripheral pattern had a 130% greater risk of death (HR=2.30, P=0.02). CDC25B protein expression scores in subjects with esophageal biopsies diagnosed as normal (n=35), dysplastic (n=23), or ESCC (n=32) increased significantly with morphologic progression. For LAMC2, all normal and dysplastic patients had a continuous pattern of protein expression, while all ESCCs showed alternative, non-continuous patterns. This series of studies showed that both CDC25B and LAMC2 over-express RNA and protein in a significant majority of ESCC cases. The strong relation of LAMC2 pattern of protein expression to survival suggests a role in prognosis, while CDC25B’s association with morphologic progression indicates a potential role as an early detection marker.
doi:10.1158/1055-9965.EPI-06-0666
PMCID: PMC2729558  PMID: 18559558
esophageal cancer; quantitative RT-PCR; tissue microarray; survival; early detection; CDC25B; LAMC2
BMC Cancer  2009;9:269.
Background
Family 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.
Methods
600 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.
Results
Increased 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).
Conclusion
These data provide strong evidence that shared susceptibility is involved in esophageal carcinogenesis and also suggest a role in prognosis.
doi:10.1186/1471-2407-9-269
PMCID: PMC2729777  PMID: 19656375
BMC Cancer  2006;6:33.
Background
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors and typically presents at an advanced and rapidly fatal stage. To better understand the role of genetics in the etiology and prevention of ESCC and to identify potential susceptibility genes as well as early detection markers, we previously compared tumor and matched normal tissues from ESCC patients from a high-risk area of China using cDNA expression microarrays and identified 41 differentially-expressed genes (13 over-expressed and 28 under-expressed).
Methods
In the current study, we validated and quantitated differential mRNA expression in a sample of nine of these 41 genes, including four that were over-expressed (SPARC, FADD, Fascin, COL7A1), and five that were under-expressed (CK4, TGM3, ECM1, PPL, EVPL), in 75 new ESCC patients using quantitative Real-time RT-PCR and the 2-ΔΔCT method to examine both tumor and matched normal tissue. In addition, we examined expression patterns for these genes by selected demographic and clinical characteristics.
Results
Four previously over-expressed (tumor ≥2-fold normal) genes were all increased in the majority of new ESCC patients: SPARC was increased in 71% of patients, Fascin in 70%, FADD in 63%, and COL7A1 in 57%. Five previously under-expressed (tumor ≤0.5-fold normal) genes similarly showed decreased mRNA expression in two-thirds or more of patients: CK4 was decreased in 83% of patients, TGM3 in 77%, ECM1 in 73%, and PPL and EVPL in 67% each. In subset analyses, associations with age (for COL7A1), family history (for PPL and ECM1), and alcohol use (for SPARC and Fascin) were also noted.
Conclusion
These data indicate that these nine genes have consistent differential mRNA expression, validating results of our previous cDNA array results, and affirming their potential role in the early detection of ESCC.
doi:10.1186/1471-2407-6-33
PMCID: PMC1386690

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