PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (66)
 

Clipboard (0)
None
Journals
more »
Year of Publication
more »
Document Types
1.  Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma 
Introduction
Poor oral health and tooth loss have been proposed as possible risk factors for some chronic diseases, including gastric cancer. However only a small number of studies have tested these associations.
Method
We conducted a case-control study in Golestan Province, Iran, that enrolled 309 cases diagnosed with gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-locations) and 613 sex, age and neighborhood matched controls. Data on oral health were obtained through physical examination and questionnaire including tooth loss, the number of decayed, missing, and filled teeth, and frequency of tooth brushing. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models adjusted for potential confounders. Standard one degree-of-freedom linear trend test and a multiple degree of freedom global test of the effect of adding oral hygiene variables to the model were also calculated.
Results
Our results showed apparent associations between tooth loss and DMFT score with risk of gastric cancer, overall and at each anatomic subsite. However, these associations were not monotonic and were strongly confounded by age. The results also showed that subjects who brushed their teeth less than daily were at significantly higher risk for gastric cardia adenocarcinoma OR (95% CI) of 5.6 (1.6–19.3).
Discussion
We found evidence for an association between oral health and gastric cancer, but the non- monotonic association, the relatively strong effect of confounder adjustment, and inconsistent results across studies must temper the strength of any conclusions.
doi:10.1158/1940-6207.CAPR-12-0491
PMCID: PMC3644330  PMID: 23503651
Adenocarcinoma; Tooth loss; Oral health; Stomach
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.  A U-shaped relationship between haematocrit and mortality in a large prospective cohort study 
Background Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values.
Methods Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate ∼99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals.
Results There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study.
Conclusions Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low- and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT.
doi:10.1093/ije/dyt013
PMCID: PMC3619954  PMID: 23569195
Anaemia; cancer; cardiovascular disease; erythrocytosis; haematocrit; mortality
4.  Squamous dysplasia – the precursor lesion for esophageal squamous cell carcinoma 
Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all esophageal cancers worldwide, and esophageal squamous dysplasia (ESD) is the only histopathology that predicts the development of ESCC. The prevalence of ESD parallels rates of invasive ESCC, and is typically found in 25% or more of adults above the age of 35 years in populations in north central China, where risk for ESCC is among the highest in the world. Results of chemoprevention and early detection studies to prevent progression of ESD suggest that these approaches, coupled with emerging endoscopic therapies, offer promise for the prevention of esophageal cancer mortality in high-risk populations. Future research on ESD and ESCC should focus on finding additional modifiable risk factors and on identifying biomarkers to incorporate into early detection strategies.
doi:10.1158/1055-9965.EPI-12-1347
PMCID: PMC3681095  PMID: 23549398
5.  Smoking water-pipe, chewing nass, and prevalence of heart disease – A cross-sectional analysis of baseline data from the Golestan Cohort Study, Iran 
Heart (British Cardiac Society)  2012;99(4):272-278.
Objective
Water-pipe and smokeless tobacco use have been associated with several adverse health outcomes. However, little information is available on the association between water-pipe use and heart disease (HD). Therefore, we investigated the association of smoking water-pipe and chewing nass (a mixture of tobacco, lime, and ash) with prevalent HD.
Design
Cross-sectional study.
Setting
Baseline data (collected in 2004–2008) from a prospective population-based study in Golestan Province, Iran.
Participants
50,045 residents of Golestan (40–75 years old; 42.4% male).
Main outcome measures
ORs and 95% CIs from multivariate logistic regression models for the association of water-pipe and nass use with HD prevalence.
Results
A total of 3051 (6.1%) participants reported a history of HD, and 525 (1.1%) and 3726 (7.5%) reported ever water-pipe or nass use, respectively. Heavy water-pipe smoking was significantly associated with HD prevalence (highest level of cumulative use versus never use, OR= 3.75; 95% CI 1.52 – 9.22; P for trend= 0.04). This association persisted when using different cutoff points, when restricting HD to those taking nitrate compound medications, and among never cigarette smokers. There was no significant association between nass use and HD prevalence (highest category of use versus never use, OR= 0.91; 95% CI 0.69 – 1.20).
Conclusions
Our study suggests a significant association between HD and heavy water-pipe smoking. Although the existing evidence suggesting similar biological consequences of water-pipe and cigarette smoking make this association plausible, results of our study were based on a modest number of water-pipe users and need to be replicated in further studies.
doi:10.1136/heartjnl-2012-302861
PMCID: PMC3671096  PMID: 23257174
hookah; ischemic heart disease; nass; tobacco; water-pipe
6.  Alcohol and acetaldehyde in African fermented milk mursik – A possible etiological factor for high incidence of esophageal cancer in western Kenya 
Background
Esophageal cancer is unusually frequent in western Kenya, despite the low prevalence of classical risk factors such as heavy drinking and tobacco smoking. Among Kenyans consumption of fermented milk is an old tradition. Our hypothesis is that alcohol and acetaldehyde are produced during the fermentation process and that their carcinogenic potential contributes to the high incidence of esophageal cancer.
Methods
Eight samples of mursik milk starter cultures were collected from different Kalenjin families in the Rift Valley province, Western Kenya. A protocol provided by the families was used for milk fermentation. Ethanol and acetaldehyde levels were measured by gas chromatography. The microbial flora in starter cultures was identified by 16S and 18S sequencing.
Results
7/8 starter cultures produced mutagenic (>100 µM) levels of acetaldehyde and 4/8 starter cultures produced >1000 µM of acetaldehyde. The highest alcohol levels (mean 79.4 mM) were detected in the four fermented milks with highest acetaldehyde production. The mean number of microbial species in the starter cultures was 5 (range 2–8). Yeasts were identified in all starter cultures (mean 1.5 species/milk) but their proportion of the total microbial count varied markedly (mean 35%, range 7–90%). A combination of yeast and lactobacilli, especially Candida krusei with Lactobacillus kefiriwith the exclusion of other species, seemed to correlate with higher acetaldehyde and ethanol levels.
Conclusions
Significant levels of ethanol and acetaldehyde were produced during mursik fermentation.
Impact
When ingested several times daily the repeated exposure to carcinogenic levels of acetaldehyde may contribute to esophageal carcinogenesis.
doi:10.1158/1055-9965.EPI-12-0908
PMCID: PMC3538938  PMID: 23155139
Candida; carcinogenesis; ethanol; fermented milk; lactobacilli
7.  The gastro-esophageal malignancies in Northern Iran research project: impact on the health research and health care systems in Iran 
Archives of Iranian medicine  2013;16(1):46-53.
Since 2000, considerable progress has been made in health research in Iran. An example of this progress has been the Gastro- Esophageal Malignancies in Northern Iran (GEMINI). The original aim of this project was to identify etiologic factors and prevention measures for upper gastrointestinal cancers in Northern provinces of Iran, but its achievements have gone much beyond the initial goal. This project is one of the largest studies in the Middle East and North African region, has helped build and strengthen research capacity at both individual and institutional levels in Iran, and has provided international credibility to research institutes and the wider research system in Iran. The success of GEMINI reveals the feasibility of large-scale studies in developing countries and serves as a successful model not only for health research institutes within Iran, but also for research systems in other developing countries. The outcomes of the project are numerous, including establishment of research networks, development of efficient methods for planning and implementation of research projects, and introduction of methodologies for project management, data management and usage of health technology. Finally and perhaps most importantly, GEMINI is among the few projects that has had a significant impact on the attitudes and concerns of decision makers in the health sector in Iran. It signifies the importance of investment in human resources and has proved that health policies should be health-based rather than patient-based. Here we review the impact of GEMINI on the health research system and the broader health care system of Iran and put these into a more global perspective.
PMCID: PMC3659328  PMID: 23273237
research design; prospective studies; pilot projects; feasibility studies; planning techniques; methods; cancer epidemiology; gastroenterology
8.  Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population 
Journal of hypertension  2013;31(7):1364-1371.
Background
There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS).
Methods
Enrollment in this study occurred in 2004–2008, and included 50,045 healthy subjects from Golestan Province in northeastern Iran. Hypertension was defined as a systolic blood pressure (SBP) ≥140, a diastolic blood pressure (DBP) ≥90, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score.
Results
Of the total cohort participants, 21,350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95%CI: 38.3%–45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive subjects, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated subjects had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese subjects, and those with a higher wealth score.
Conclusions
Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended.
doi:10.1097/HJH.0b013e3283613053
PMCID: PMC3766446  PMID: 23673348
hypertension; awareness; obesity; smoking; socioeconomic status
9.  A prospective study of polymorphisms of DNA repair genes XRCC1, XPD23 and APE/ref‐1 and risk of stroke in Linxian, China 
Background
Stroke is the leading cause of death in Linxian, China. Although there is evidence of DNA damage in experimental stroke, no data exist on DNA repair and stroke in human populations.
Aim
To assess the risk of stroke conferred by polymorphisms in the DNA repair genes, XRCC1, XPD23 and APE/ref‐1 in a cohort of individuals originally assembled as subjects in two cancer prevention trials in Linxian, China.
Methods
The subjects for this prospective study were sampled from a cohort of 4005 eligible subjects who were alive and cancer free in 1991 and had blood samples available for DNA extraction. Using real‐time Taqman analyses, all incident cases of stroke (n = 118) that developed from May 1996, and an age‐ and a sex‐stratified random sample (n = 454) drawn from all eligible subjects were genotyped. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% CIs.
Results
No association was observed between polymorphisms in APE/ref‐1 codon 148 and XRCC1*6 codon 194, and stroke. Polymorphisms in XRCC1*10 codon 399 were associated with a significantly reduced risk of stroke (RR 0.59, 95% CI 0.36 to 0.96, p = 0.033), whereas XPD23 codon 312 was associated with a significantly increased risk of stroke (RR 2.18, 95% CI 1.14 to 4.17, p = 0.010).
Conclusions
Polymorphisms in DNA repair genes may be important in the aetiology of stroke. These data should stimulate research on DNA damage and repair in stroke.
doi:10.1136/jech.2006.048934
PMCID: PMC2653006  PMID: 17630376
10.  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
11.  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
12.  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
13.  A multi-day environmental study of polycyclic aromatic hydrocarbon exposure in a high-risk region for esophageal cancer in China 
Linzhou, China has one of the highest rates of esophageal squamous cell carcinoma in the world. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), may play a role in this increased risk. To better understand PAH sources, we measured PAHs in the air and food of 20 non-smokers over multiple days and compared the concentrations to a urinary PAH biomarker, 1-hydroxypyrene glucuronide (1-OHPG). Sampling occurred over four consecutive days. Kitchen air samples (days 2–3) and duplicate diet samples (days 1–4) were analyzed for 14 or more unique PAHs, including BaP. Daily urine samples (days 1–3) were analyzed for 1-OHPG. Mixed-effects models were used to evaluate the associations between air or food PAH concentrations and urine 1-OHPG concentrations. The median kitchen air BaP concentration was 10.2 ng/m3 (inter-quartile range (IQR): 5.1–20.2 ng/m3). The median daily food BaP concentration and intake were 0.08 ng/g (IQR=0.04–0.16 ng/g) and 86 ng/day (IQR=41–142 ng/day), respectively. The median 1-OHPG concentration was 3.36 pmol/mL (IQR=2.09–6.98 pmol/mL). In mixed-effects models, 1-OHPG concentration increased with same-day concentration of food BaP (p=0.07). Though PAH concentrations in air were not associated with 1-OHPG concentrations, the high concentrations of PAHs in both air and food suggest that they are both important routes of exposure to PAHs in this population. Further evaluation of the role of PAH exposure from air and food in the elevated rates of esophageal cancer in this region is warranted.
doi:10.1038/jes.2012.73
PMCID: PMC3504638  PMID: 22805987
polycyclic aromatic hydrocarbons; cancer; China; dietary exposure; inhalation exposure; biomonitoring; multimedia exposure assessment
14.  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
15.  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
16.  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
17.  Significant variation in the concentration of carcinogenic polycyclic aromatic hydrocarbons in yerba maté samples by brand, batch and processing method 
Environmental science & technology  2012;46(24):13488-13493.
Drinking maté, common in southern South America, may increase the risk of esophageal squamous cell carcinoma (ESCC). In 2006, we found high but variable polycyclic aromatic hydrocarbon (PAH) content in commercial yerba maté samples from eight Brazilian brands. The PAH content of new samples from the same brands, purchased in 2008, and four brands from a single manufacturer processed in different ways, obtained in 2010, were quantified to determine whether PAH concentration was still high, PAH content variation was brand specific, and whether processing method affects PAH content of commercial yerba maté. Concentrations of individual PAHs were quantified using gas chromatography/mass spectrometry with deuterated PAHs as internal standards. Median total PAH concentration was 1500 ng/g (range: 625 to 3710 ng/g) and 1090 ng/g (621 to 1990 ng/g) in 2008 and 2010 samples, respectively. Comparing 2006 and 2008 samples, some brands had high PAH concentrations in both years, while PAH concentration changed considerably in others. Benzo[a]pyrene concentrations ranged from 11.9 to 99.3 ng/g and 5.11 to 21.0 ng/g in 2008 and 2010 samples, respectively. The 2010 sample processed without touching smoke had the lowest benzo[a]pyrene content. These results support previous findings of very high total and carcinogenic PAH concentrations in yerba maté, perhaps contributing to the high incidence of ESCC in southern South America. The large PAH content variation by brand, batch and processing method suggests it may be possible to reduce the content of carcinogenic PAHs in commercial yerba maté, making it a healthier beverage.
doi:10.1021/es303494s
PMCID: PMC3525749  PMID: 23101992
Polycyclic Aromatic Hydrocarbons; Yerba Maté; Carcinogens; Esophageal Cancer; Benzo(α)pyrene; Processing Method; Lifestyle
18.  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
19.  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
20.  Parameters predicting lymph node metastasis in patients with superficial esophageal squamous cell carcinoma 
Endoscopic resection is a less invasive treatment than esophagectomy for superficial esophageal squamous cell carcinoma, but patients with lymph node metastasis need additional treatment after endoscopic resection. The purpose of this study was to establish a set of indicators to identify superficial esophageal squamous cell carcinoma patients at a high risk of metastasis. 271 superficial esophageal squamous cell carcinoma esophagectomy cases were reviewed retrospectively. The relationships between clinicopathological parameters and immunohistochemical findings (p53, Cyclin D1, EGFR and VEGF) on tissue microarrays, on the one hand, and lymph node metastasis were assessed by univariate and multivariate logistic regression analyses. Patients with intraluminal masses and ulcerated masses had a high risk of lymph node metastasis. Patients with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology had almost no risk of lymph node metastasis. We recommend endoscopic resection for all erosive, papillary and plaque-like superficial esophageal squamous cell carcinomas where endoscopic resection is clinically feasible, and esophagectomy for all other erosive, papillary and plaque-like cases and all intraluminal masses and ulcerated tumors. No additional treatment is needed for endoscopic resection cases with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology. These clinical and pathological criteria should enable more accurate selection of patients for these procedures.
doi:10.1038/modpathol.2012.89
PMCID: PMC3505024  PMID: 22627741
superficial cancer; esophageal cancer; squamous cell carcinoma; endoscopic resection; lymph node metastasis
21.  Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus 
Gastrointestinal endoscopy  2011;74(6):1181-1190.
Background
Radiofrequency ablation (RFA) is safe and effective for eradicating neoplasia in Barrett’s esophagus.
Objective
Evaluate RFA for eradicating early esophageal squamous cell neoplasia (ESCN) defined as moderate- and high-grade squamous intraepithelial neoplasia (MGIN, HGIN) and early flat-type esophageal squamous cell carcinoma (ESCC).
Design
Prospective cohort study.
Setting
Tertiary referral center.
Patients
Esophageal unstained lesions (USLs) were identified using Lugol’s chromoendoscopy. Inclusion: at least 1 flat (type 0-IIb) USL ≥3cm, USL-bearing esophagus ≤12 cm, and a consensus diagnosis of MGIN, HGIN, or ESCC by two expert GI pathologists. Exclusion: prior endoscopic resection or ablation, stricture, or any non-flat mucosa.
Interventions
Circumferential RFA creating a continuous treatment area (TA) including all USLs. At 3-month intervals thereafter, chromoendoscopy with biopsies, followed by focal RFA of USLs, if present.
Main outcome measures
Complete response (CR) at 12 months, defined as absence of MGIN, HGIN or ESCC in TA; CR after one RFA session; neoplastic progression from baseline; and adverse events.
Results
29 patients (14 male, mean age 60.3 years) with MGIN (18), HGIN (10), or ESCC (1) participated. Mean USL length was 6.2 cm (TA 8.2 cm). At 3-months, after one RFA session, 86% of patients (25/29) were CR. At 12-months, 97% (28/29) of patients were CR. There was no neoplastic progression. There were 4 strictures, all dilated to resolution.
Limitations
Single center study with limited number of patients.
Conclusions
In patients with early ESCN (MGIN, HGIN, flat-type ESCC), RFA was associated with a high rate of histological complete response (97% of patients), no neoplastic progression, and an acceptable adverse event profile.
doi:10.1016/j.gie.2011.05.024
PMCID: PMC3505032  PMID: 21839994
22.  Frequent occurrence of esophageal cancer in young people in western Kenya 
Esophageal cancer has a strikingly uneven geographical distribution, resulting in focal endemic areas in several countries. One such endemic area is in western Kenya. We conducted a retrospective review of all pathology-confirmed malignancies diagnosed at Tenwek Hospital, Bomet District, between January 1999 and September 2007. Tumor site, histology, sex, age, ethnicity, and location of residence were recorded. Cases were analyzed within and outside a traditional catchment area defined as ≤ 50 km from the hospital. Since 1999, the five most common cancer sites were esophagus, stomach, prostate, colorectum, and cervix. Esophageal cancer accounted for 914 (34.6%) of the 2643 newly diagnosed cancers, and showed increasing trends within and outside the catchment area. Fifty-eight (6.3%) patients were ≤ 30 years old and 9 (1%) were ≤ 20 years old; the youngest patient was 14 at diagnosis. Young cases (≤30) were more common among patients of Kalenjin ethnicity (9.2%) than among other ethnicities (1.7%) (odds ratio (95%CI) 5.7 (2.1–15.1)). This area of western Kenya is a high-risk region for esophageal cancer, and appears unique in its large proportion of young patients. Our findings support the need for further study of both environmental and genetic risk factors for esophageal cancer in this area.
doi:10.1111/j.1442-2050.2009.00977.x
PMCID: PMC3505035  PMID: 19473205
Esophageal cancer; Kenya; age of onset; ethnicity
23.  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
24.  Prospective Study of Serum Cysteine Levels and Oesophageal and Gastric Cancers in China 
Gut  2011;60(5):618-623.
Background
Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case-cohort study within the General Population Nutrition Intervention Trial in Linxian, China.
Methods
498 oesophageal squamous cell carcinomas (OSCC) and 255 gastric cardia adenocarcinomas (GCA) were matched by age and sex to 947 individuals from the wider cohort. We calculated hazard ratios (HR) and 95% confidence intervals (95% CI) using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders.
Results
Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI: 0.51, 0.98) and 0.59 for GCA (95% CI: 0.38, 0.91). These associations were dose dependent (P for trend = 0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata.
Conclusion
Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.
doi:10.1136/gut.2010.225854
PMCID: PMC3428021  PMID: 21242262
oesophageal squamous cell carcinoma; gastric cardia cancer; hazard ratio; cysteine
25.  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

Results 1-25 (66)