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1.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1093/carcin/bgt094
PMCID: PMC3697889  PMID: 23504502
2.  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.
doi:10.1093/carcin/bgt030
PMCID: PMC3643422  PMID: 23358850
3.  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
4.  PAH exposure in esophageal tissue and risk of esophageal squamous cell carcinoma in northeastern Iran 
Gut  2010;59(9):1178-1183.
Objective
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.
Design
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.
Setting
Rural region in northeastern Iran.
Participants
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.
Results
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).
Conclusions
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.
doi:10.1136/gut.2010.210609
PMCID: PMC3505022  PMID: 20584779
esophageal squamous cell carcinoma; polycyclic aromatic hydrocarbons; immunohistochemistry; tissue microarray
5.  Prospective Study of Serum 25-Hydroxyvitamin D Concentration and Mortality in a Chinese Population 
American Journal of Epidemiology  2012;176(11):1043-1050.
Prospective epidemiologic data on the association between vitamin D and mortality are limited, particularly in Asian populations. Among subjects in Linxian, China, the authors aimed to test whether baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations in a prospective cohort were associated with all-cause mortality and cause-specific mortality rates over 24 years of follow-up (1986–2010). Serum 25(OH)D concentrations were measured in 1,101 subjects using an immunoassay. Hazard ratios and 95% confidence intervals were calculated using Cox regression models that were adjusted for age, sex, tobacco smoking, alcohol drinking, and hypertension. The 25th, 50th, and 75th percentile concentrations of 25(OH)D were 19.6, 31.9, and 48.4 nmol/L, respectively. During follow-up, 793 subjects died, including 279 who died of cerebrovascular accident, 217 who died of cancer, and 200 cardiovascular disease deaths. All-cause mortality was not associated with 25(OH)D concentrations using continuous models (for every 15 nmol/L, hazard ratio = 1.01, 95% confidence interval: 0.97, 1.05) or quartile models (fourth vs. first quartiles, hazard ratio = 1.06, 95% confidence interval: 0.87, 1.30; P for trend = 0.731). The authors also found no association with the cause-specific mortality outcomes. Results were similar for men and women. This study showed that prediagnostic serum 25(OH)D concentrations were not associated with all-cause or cause-specific mortality rates in this Chinese population who had low levels of vitamin D.
doi:10.1093/aje/kws285
PMCID: PMC3571239  PMID: 23139250
cancer; cardiovascular diseases; China; mortality; vitamin D
6.  Iron in Relation to Gastric Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study 
Background
Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective ATBC Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC).
Methods
We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 non-specified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity (UIBC), and C-reactive protein. Total iron binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis.
Results
Serum iron metrics were not associated with GCC, except for a potential ‘n’-shaped relationship with TIBC (global p=0.038). GNCC was inversely associated with serum ferritin (global p=0.024), serum iron (global p=0.060) and, possibly, transferrin saturation. TIBC appeared to share a ‘u’shaped relationship with GNCC (global p=0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations.
Conclusions
We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency.
doi:10.1158/1055-9965.EPI-12-0799
PMCID: PMC3493744  PMID: 23001240
Helicobacter pylori; Iron; Nested Case-Control Studies; Prospective Studies; Stomach Neoplasms
7.  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
8.  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
9.  Fumonisin B1 and Risk of Hepatocellular Carcinoma in Two Chinese Cohorts 
Food and Chemical Toxicology  2011;50(3-4):679-683.
Fumonisin B1 (FB1), a mycotoxin that contaminates corn in certain climates, has been demonstrated to cause hepatocellular cancer (HCC) in animal models. Whether a relationship between FB1 and HCC exists in humans is not known. To examine the hypothesis, we conducted case-control studies nested within two large cohorts in China; the Haimen City Cohort and the General Population Study of the Nutritional Intervention Trials cohort in Linxian. In the Haimen City Cohort, nail FB1 levels were determined in 271 HCC cases and 280 controls. In the General Population Nutritional Intervention Trial, nail FB1 levels were determined in 72 HCC cases and 147 controls. In each population, odds ratios and 95% confidence intervals (95%CI) from logistic regression models estimated the association between measurable FB1 and HCC, adjusting for hepatitis B virus infection and other factors. A meta-analysis that included both populations was also conducted. The analysis revealed no statistically significant association between FB1 and HCC in either Haimen City (OR=1.10, 95%CI=0.64–1.89) or in Linxian (OR=1.47, 95%CI=0.70–3.07). Similarly, the pooled meta-analysis showed no statistically significant association between FB1 exposure and HCC (OR=1.22, 95%CI=0.79–1.89). These findings, although somewhat preliminary, do not support an associated between FB1 and HCC.
doi:10.1016/j.fct.2011.11.029
PMCID: PMC3299856  PMID: 22142693
fumonisin; hepatocellular carcinoma; cohort study; China; epidemiology
10.  InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers 
Background
The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer.
Methods
We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided.
Results
We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036).
Conclusions
We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
doi:10.1093/jnci/djr499
PMCID: PMC3260131  PMID: 22228147
11.  Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma 
Gut  2011;61(11):1533-1537.
Background
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
Methods
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
Results
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
Conclusion
Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
doi:10.1136/gutjnl-2011-300653
PMCID: PMC3462270  PMID: 22180062
ghrelin; oesophageal squamous cell carcinoma; atrophy
12.  Serum thyroglobulin, a biomarker for iodine deficiency, is not associated with increased risk of upper gastrointestinal cancers in a large Chinese cohort 
Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. This study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA, and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from approximately 200 subjects of each case type and 400 non-cases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex- and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history, and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted Hazard Ratios of 0.88 (95% confidence interval 0.50–1.52), 1.14 (0.63–2.05), and 0.78 (0.47–1.31) for GNCA, GCA, and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers.
doi:10.1002/ijc.25789
PMCID: PMC3075342  PMID: 21105043
iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China
13.  The Relationship Between Serum Ghrelin and the Risk of Gastric and Esophagogastric Junctional Adenocarcinomas 
Background
Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated.
Methods
We conducted a nested case–control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric noncardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided.
Results
Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements.
Conclusion
Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis.
doi:10.1093/jnci/djr194
PMCID: PMC3139586  PMID: 21693726
14.  Diabetes Mellitus and Its Correlates in an Iranian Adult Population 
PLoS ONE  2011;6(10):e26725.
The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention.
doi:10.1371/journal.pone.0026725
PMCID: PMC3203882  PMID: 22053206
15.  Serum pepsinogens and Helicobacter pylori in relation to the risk of esophageal squamous cell carcinoma in the ATBC Study 
Background
Helicobacter pylori (H. pylori) can induce gastric atrophy in humans, which in turn increases gastric cancer risk. Whether H. pylori and gastric atrophy also affect the risk of esophageal squamous cell carcinoma (ESCC), however, remains unresolved.
Methods
We performed a nested case-control study within the prospective ATBC Study to assess these relationships. The ATBC Study is composed of 29,133 Finnish male smokers, aged 50–69, who were recruited during 1985–1988. Using baseline sera, we assessed H. pylori status (via IgG antibodies against whole-cell and CagA antigens) and gastric atrophy status (via the biomarkers pepsinogen I (PGI) and II (PGII)) in 79 ESCC cases and 94 controls. Logistic regression with adjustment for age, date of blood draw, education, cigarette smoking, alcohol, body mass index, and fruit and vegetable intake was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI).
Results
Gastric atrophy (PGI:PGII <4) was associated with ESCC (OR=4.58, 95%CI:2.00–10.48). There was no evidence for an association between H. pylori and ESCC (OR=0.94, 95%CI:0.40–2.24).
Conclusions
These results could be explained by misclassification of H. pylori status due to serologic amnesia, ESCC risk being dependent upon the functional consequences or interactions of H. pylori, rather than the infection per se, gastric atrophy having a different histogenesis in ESCC without being primarily dependent upon H. pylori acquisition, or a lack of statistical power to detect an effect.
Impact
Validation of these results may warrant mechanistic studies to determine the route of association between gastric atrophy and ESCC.
doi:10.1158/1055-9965.EPI-10-0270
PMCID: PMC2919643  PMID: 20647397
Atrophy; Esophageal Neoplasms; Helicobacter pylori; Nested Case-Control Studies; Pepsinogens; Prospective Studies
16.  Serum cytokine analysis in a positive chemoprevention trial: Selenium, Interleukin-2 and an association with squamous preneoplastic disease 
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
17.  No role for human papillomavirus in esophageal squamous cell carcinoma in China 
Certain regions of China have high rates of esophageal squamous cell carcinoma (ESCC). Previous studies of human papillomavirus (HPV), a proposed causal factor, have produced highly variable results. We attempted to evaluate HPV and ESCC more definitively using extreme care to prevent DNA contamination. We collected tissue and serum in China from 272 histopathologically-confirmed ESCC cases with rigorous attention to good molecular biology technique. We tested for HPV DNA in fresh-frozen tumor tissue using PCR with PGMY L1 consensus primers and HPV16 and 18 type-specific E6 and E7 primers, and in formalin-fixed paraffin-embedded tumor tissue using SPF10 L1 primers. In HPV-positive cases, we evaluated p16INK4a overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity. β-globin, and thus DNA, was adequate in 98.2% of the frozen tumor tissues (267/272). Of these, 99.6% (95% confidence interval (CI) = 97.9–100.0%) were negative for HPV DNA by PGMY, and 100% (95% CI = 98.6–100%) were negative by HPV16/18 E6/E7 PCR. In the corresponding formalin-fixed paraffin-embedded tumor specimens, 99.3% (95% CI = 97.3–99.9%) were HPV negative by SPF10. By PGMY, 1 case tested weakly positive for HPV89, a noncancer causing HPV type. By SPF10, 2 cases tested weakly positive: 1 for HPV16 and 1 for HPV31. No HPV DNA-positive case had evidence of HPV oncogene activity as measured by p16INK4a overexpression or E6/E7 seropositivity. This study provides the most definitive evidence to date that HPV is not involved in ESCC carcinogenesis in China. HPV DNA contamination cannot be ruled out as an explanation for high HPV prevalence in ESCC tissue studies with less stringent tissue procurement and processing protocols.
doi:10.1002/ijc.25023
PMCID: PMC3069961  PMID: 19918949
human papillomavirus; esophageal squamous cell carcinoma
18.  The Gastric Cardia is not a Target for Human Papillomavirus-induced Carcinogenesis 
Background
Thousands of people in central Asia die every year from gastric cardia adenocarcinoma (GCA). GCA arises in the transformation zone between the esophagus and the stomach, similar to cervical and oropharyngeal carcinoma, which arise in areas with transformation zone characteristics. The analogous biology of the gastric cardia to the cervix and oropharynx, where human papillomavirus (HPV) is known to cause cancer, raises the possibility that GCA could be an HPV-associated cancer. Given the availability of an effective HPV vaccine and its potential to prevent HPV-associated cancer, we decided to evaluate the prevalence of HPV DNA in GCA.
Methods
We collected tumor tissue from 144 histopathologically-confirmed GCA patients at Yaocun Commune Hospital, Linxian, China, with rigorous attention to prevent DNA contamination. We tested for the presence of HPV DNA in fresh-frozen tumor specimens using PCR with sensitive L1, E6, and E7-based primers.
Results
DNA was adequate, as indicated by β-globin positivity, in 108 cases. Of these, all (100%, 95% confidence interval: 97%–100%) were negative for HPV DNA
Conclusions
These results suggest that HPV does not contribute to gastric cardia carcinogenesis in north central China.
Impact
Since GCA does not appear to be an HPV-associated cancer, prophylactic HPV vaccination is unlikely to affect rates of GCA in China.
doi:10.1158/1055-9965.EPI-10-0089
PMCID: PMC2852466  PMID: 20332262
19.  Serum pepsinogens and risk of gastric and esophageal cancers in the General Population Nutrition Intervention Trial cohort 
Gut  2009;58(5):636-642.
Objective
Low serum pepsinogen I (PGI) and low pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy. We aimed to prospectively test the association between serum PGI/II ratio and risks of gastric noncardia adenocarcinoma, gastric cardia adenocarcinoma, and esophageal squamous cell carcinoma.
Design
Case-cohort study nested in a prospective cohort with over 15 years of follow-up.
Setting
Rural region of the People’s Republic of China.
Subjects
Men and women aged 40-69 at study baseline.
Main outcome measures
Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and caner risk
Results
Compared to subjects with PGI/II ratio of > 4, those with ≤4 had HRs (95%CIs) of 2.72 (1.77-4.20) and 2.12 (1.42-3.16) for noncardia and cardia gastric cancers, respectively. Risk of both cancers were also increased when other cut points ranging from 3 to 6, or when we used quartile models, or nonlinear continuous models. Risk of ESCC was marginally increased in those with PGI/II ratio ≤4, with HR (95% CI) of 1.56 (0.99-2.47), but quartile models and continuous models showed no increased risk. The nonlinear continuous models suggested that any single cut point collapsed subjects with dissimilar gastric cancer risks, and that using cut points was not an efficient use of data in evaluating these associations.
Conclusion
In this prospective study, we found similar and significantly increased risks of noncardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio, but little evidence for an association with ESCC risk.
doi:10.1136/gut.2008.168641
PMCID: PMC2792746  PMID: 19136509
Gastric cancer; Esophageal cancer; Pepsinogen; Case-cohort
20.  Total and Cancer Mortality After Supplementation With Vitamins and Minerals: Follow-up of the Linxian General Population Nutrition Intervention Trial 
Background
The General Population Nutrition Intervention Trial was a randomized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991, in which 29 584 adult participants in Linxian, China, were given daily vitamin and mineral supplements. Treatment with “factor D,” a combination of 50 μg selenium, 30 mg vitamin E, and 15 mg beta-carotene, led to decreased mortality from all causes, cancer overall, and gastric cancer. Here, we present 10-year follow-up after the end of active intervention.
Methods
Participants were assessed by periodic data collection, monthly visits by village health workers, and quarterly review of the Linxian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models.
Results
Through May 31, 2001, 276 participants were lost to follow-up; 9727 died, including 3242 from cancer (1515 from esophageal cancer and 1199 from gastric cancer). Participants who received factor D had lower overall mortality (HR = 0.95, 95% CI = 0.91 to 0.99; P = .009; reduction in cumulative mortality from 33.62% to 32.19%) and gastric cancer mortality (HR = 0.89, 95% CI = 0.79 to 1.00; P = .043; reduction in cumulative gastric cancer mortality from 4.28% to 3.84%) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years. Esophageal cancer deaths between those who did and did not receive factor D were not different overall; however, decreased 17% among participants younger than 55 (HR = 0.83, 95% CI = 0.71 to 0.98; P = .025) but increased 14% among those aged 55 years or older (HR = 1.14, 95% CI = 1.00 to 1.30; P = .47). Vitamin A and zinc supplementation was associated with increased total and stroke mortality; vitamin C and molybdenum supplementation, with decreased stroke mortality.
Conclusion
The beneficial effects of selenium, vitamin E, and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants. Late effects of other supplementation regimens were also observed.
doi:10.1093/jnci/djp037
PMCID: PMC2664089  PMID: 19318634
21.  Serum 25(OH)-Vitamin D concentration and risk of esophageal squamous dysplasia 
Background
Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma (ESCC), and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures of vitamin D exposure have reached different conclusions about the association between vitamin D and risk of developing esophageal cancer.
Methods
We measured serum 25-hydroxyvitamin D (25(OH)D) concentrations in a cross-sectional analysis of 720 subjects from Linxian, China, a population at high risk for developing ESCC. All subjects underwent endoscopy and biopsy and were categorized by presence or absence of histologic squamous dysplasia. We used crude and multivariate adjusted generalized linear models to estimate the relative risk (RR) and 95% confidence intervals (CI) for the association between squamous dysplasia and sex-specific quartiles of serum 25(OH)D concentration.
Results
Two hundred and thirty (32%) of 720 subjects had squamous dysplasia. Subjects with dysplasia had significantly higher median serum 25(OH)D concentrations then subjects without dysplasia, 36.5 and 31.5 nmol/L respectively (Wilcoxon two-sample test p = 0.0004). In multivariate adjusted models, subjects in the highest compared to the lowest quartile were at significantly increased risk of squamous dysplasia, RR (95% CI) = 1.86 (1.35–2.62). Increased risks were similar when examined in men and women separately: Men RR (95% CI) = 1.74 (1.08–2.93); Women RR (95% CI) = 1.96 (1.28–3.18).
Conclusions
Higher serum 25(OH)D concentration was associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding.
doi:10.1158/1055-9965.EPI-07-0461
PMCID: PMC2812415  PMID: 17855710
Esophageal cancer; Squamous dysplasia; Vitamin D; Serum 25(OH)D; China
22.  Hepatitis C Virus Infection, Linxian, China1 
Emerging Infectious Diseases  2005;11(1):17-21.
The prevalence of HCV infection was high among older citizens of Linxian, China, in 2000.
Bloodborne viruses may have spread in rural China during the past 25 years, but population-based prevalence estimates are lacking. We examined the frequency of hepatitis C virus (HCV) and HIV type 1 (HIV-1) among residents of Linxian, a rural community in Henan Province. In 2000, blood was collected from participants (>55 years of age) who had enrolled in a population-based nutritional intervention trial in 1985. We randomly selected 500 participants for HCV testing and 200 participants for HIV-1 testing. For HCV, 48 (9.6%) of 500 participants were positive by enzyme immunoassay and recombinant immunoblot assay (95% confidence interval [CI], 7.0%–12.2%), and prevalence was lowest in the most geographically isolated participants. Among the HCV-infected participants, 42 had a specimen available from1985, of which 16 (38.1%) were positive for HCV. For HIV-1, 0/200 participants were positive. We conclude that HCV is now a common infection among older adults in Linxian, China.
doi:10.3201/eid1101.031005
PMCID: PMC3294338  PMID: 15705317
AIDS; China; epidemiology; hepatitis B virus (HBV); hepatitis C virus (HCV); human immunodeficiency virus type 1 (HIV-1); liver cancer; prevalence; research

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