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1.  Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women 
Journal of Clinical Oncology  2013;31(12):1548-1553.
Purpose
We recently reported an inverse association between soy food intake and lung cancer risk among nonsmoking women. The effect size for aggressive lung cancers was larger than that observed for other types of lung cancer. Therefore, we hypothesized that soy consumption may favorably affect the overall survival of patients with lung cancer.
Patients and Methods
This analysis included 444 women with incident lung cancer identified from the Shanghai Women's Health Study. Prediagnosis soy food intake was assessed at enrollment and reassessed 2 years later. Proportional hazards models were used to evaluate the association between soy food intake and overall survival.
Results
Of the 444 patients with lung cancer, 318 died during follow-up. Initial analyses including all patients showed that higher intake of soy food was associated with better overall survival after adjusting for demographic and lifestyle characteristics and other nonclinical factors. Larger effect sizes for the association were found after additional adjustment for tumor stage and treatment in analyses including 301 patients with data available on these clinical factors. Compared with the median intake of soy food, fully adjusted hazard ratios for total mortality associated with the 10th, 30th, 70th, and 90th percentiles of intake were 1.81 (95% CI, 1.26 to 2.59), 1.25 (95% CI, 1.09 to 1.42), 0.88 (95% CI, 0.80 to 0.97), and 0.89 (95% CI, 0.68 to 1.16), respectively. Similar inverse associations were observed for dietary isoflavone intake.
Conclusion
This study suggests, to the best of our knowledge for the first time, that, among women with lung cancer, prediagnosis intake of soy food is associated with better overall survival.
doi:10.1200/JCO.2012.43.0942
PMCID: PMC3625711  PMID: 23530109
2.  Principal component analysis of dietary and lifestyle patterns in relation to risk of subtypes of esophageal and gastric cancer 
Annals of epidemiology  2011;21(7):543-550.
Purpose
To perform pattern analyses of dietary and lifestyle factors in relation to risk of esophageal and gastric cancers.
Methods
We evaluated risk factors for esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and other gastric cancers (OGA) using data from a population-based case-control study conducted in Connecticut, New Jersey, and western Washington state. Dietary/lifestyle patterns were created using principal component analysis (PCA). Impact of the resultant scores on cancer risk was estimated through logistic regression.
Results
PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score. Risk of EA increased with increasing GERD/BMI score, and risk of ESCC rose with increasing smoking/alcohol score and decreasing GERD/BMI score. Fruit/vegetable scores were inversely associated with EA, ESCC, and GCA.
Conclusions
PCA may provide a useful approach for summarizing extensive dietary/lifestyle data into fewer interpretable combinations that discriminate between cancer cases and controls. The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, while fruit/vegetable intake reduces risk of EA, ESCC, and GCA. GERD/obesity were confirmed as risk factors for EA and smoking/alcohol as risk factors for ESCC.
doi:10.1016/j.annepidem.2010.11.019
PMCID: PMC3109225  PMID: 21435900
esophageal adenocarcinoma; gastric cardia adenocarcinoma; esophageal squamous cell carcinoma; diet; principal components
3.  Night-Shift Work and Breast Cancer Risk in a Cohort of Chinese Women 
American Journal of Epidemiology  2010;171(9):953-959.
Shift work involving disruption of circadian rhythms has been classified as a probable cause of human cancer by the International Agency for Research on Cancer, based on limited epidemiologic evidence and abundant experimental evidence. The authors investigated this association in a population-based prospective cohort study of Chinese women. At baseline (1996–2000), information on lifetime occupational history was obtained from 73,049 women. Lifetime night-shift exposure indices were created using a job exposure matrix. During 2002–2004, self-reported data on frequency and duration of night-shift work were collected. Hazard ratios and 95% confidence intervals, adjusted for major breast cancer risk factors, were calculated. During follow-up through 2007, 717 incident cases of breast cancer were diagnosed. Breast cancer risk was not associated with ever working the night shift on the basis of the job exposure matrix (adjusted hazard ratio = 1.0, 95% confidence interval: 0.9, 1.2) or self-reported history of night-shift work (adjusted hazard ratio = 0.9, 95% confidence interval: 0.7, 1.1). Risk was also not associated with frequency, duration, or cumulative amount of night-shift work. There were no indications of effect modification. The lack of an association between night-shift work and breast cancer adds to the inconsistent epidemiologic evidence. It may be premature to consider shift work a cause of cancer.
doi:10.1093/aje/kwq029
PMCID: PMC2877476  PMID: 20375193
breast neoplasms; China; prospective studies; work schedule tolerance
4.  Contemporary Renal Cell Cancer Epidemiology 
Cancer journal (Sudbury, Mass.)  2008;14(5):288-301.
We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to TCE has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the VHL gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers.
doi:10.1097/PPO.0b013e3181867628
PMCID: PMC3077538  PMID: 18836333
renal cell cancer; incidence trends; cohort studies; smoking; obesity; hypertension; diet; occupation; genetic polymorphism; somatic mutation
5.  Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women 
Gut  2007;56(12):1671-1677.
Background
Gastric cancer incidence rates are consistently lower in women than men in both high and low‐risk regions worldwide. Sex hormones, such as progesterone and estrogen, may protect women against gastric cancer.
Objective
To investigate the association of menstrual and reproductive factors and gastric cancer risk.
Methods
These associations were prospectively investigated in 73 442 Shanghai women. After 419 260 person‐years of follow‐up, 154 women were diagnosed with gastric cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusted for age, body mass index, education, income, and cigarette use.
Results
No associations were observed between gastric cancer risk and age of menarche, number of children, breast feeding, or oral contraceptive use. In contrast, associations were observed with age of menopause (HR 0.80 per five‐year increase in menopausal age, 95% CI 0.66–0.97), years of fertility (participants with less than 30 years of fertility were at increased risk compared with those with 30–36 years of fertility, HR 1.90, 95% CI 1.25–2.90), years since menopause (HR 1.26 per five years, 95% CI 1.03–1.53), and intrauterine device use (HR for users 1.61, 95% CI 1.08–2.39).
Conclusions
These results support the hypothesis that female hormones play a protective role in gastric cancer risk.
doi:10.1136/gut.2007.129411
PMCID: PMC2095686  PMID: 17627962
stomach neoplasms; cohort studies; prospective studies; hormones
6.  Historical Occupational Trichloroethylene Air Concentrations Based on Inspection Measurements From Shanghai, China 
Annals of Occupational Hygiene  2014;59(1):62-78.
Purpose:
Trichloroethylene (TCE) is a carcinogen that has been linked to kidney cancer and possibly other cancer sites including non-Hodgkin lymphoma. Its use in China has increased since the early 1990s with China’s growing metal, electronic, and telecommunications industries. We examined historical occupational TCE air concentration patterns in a database of TCE inspection measurements collected in Shanghai, China to identify temporal trends and broad contrasts among occupations and industries.
Methods:
Using a database of 932 short-term, area TCE air inspection measurements collected in Shanghai worksites from 1968 through 2000 (median year 1986), we developed mixed-effects models to evaluate job-, industry-, and time-specific TCE air concentrations.
Results:
Models of TCE air concentrations from Shanghai work sites predicted that exposures decreased 5–10% per year between 1968 and 2000. Measurements collected near launderers and dry cleaners had the highest predicted geometric means (GM for 1986 = 150–190mg m−3). The majority (53%) of the measurements were collected in metal treatment jobs. In a model restricted to measurements in metal treatment jobs, predicted GMs for 1986 varied 35-fold across industries, from 11mg m−3 in ‘other metal products/repair’ industries to 390mg m–3 in ‘ships/aircrafts’ industries.
Conclusions:
TCE workplace air concentrations appeared to have dropped over time in Shanghai, China between 1968 and 2000. Understanding differences in TCE concentrations across time, occupations, and industries may assist future epidemiologic studies in China.
doi:10.1093/annhyg/meu066
PMCID: PMC4290627  PMID: 25180291
China; occupational exposures; population-based studies; statistical model; trichloroethylene
7.  The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling 
Purpose
We aimed to identify serum metabolites as potential valuable biomarkers for lung cancer and to improve risk stratification in smokers.
Experimental Design
We performed global metabolomic profiling followed by targeted validation of individual metabolites in a case-control design of 386 lung cancer cases and 193 matched controls. We then validated bilirubin, which consistently showed significant differential levels in cases and controls, as a risk marker for lung cancer incidence and mortality in a large prospective cohort comprised of 425,660 participants.
Results
Through global metabolomic profiling and following targeted validation, bilirubin levels consistently showed a statistically significant difference among healthy controls and lung cancer cases. In the prospective cohort, the inverse association was only seen in male smokers, regardless of smoking pack-years and intensity. Compared with male smokers in the highest bilirubin group (>1 mg/dL), those in the lowest bilirubin group (<0.75 mg/dL) had 55% and 66% increase in risks of lung cancer incidence and mortality, respectively. For every 0.1 mg/dL decrease of bilirubin, the risks for lung cancer incidence and mortality increased by 5% and 6% in male smokers, respectively (both P < 0.001). There was a significant interaction between low serum bilirubin level and smoking on lung cancer risk (P for interaction = 0.001).
Conclusion
Low levels of serum bilirubin are associated with higher risks of lung cancer incidence and mortality in male smokers and can be used to identify higher risk smokers for lung cancer.
doi:10.1158/1078-0432.CCR-14-0748
PMCID: PMC4286447  PMID: 25336700
lung cancer; smokers; metabolomics; bilirubin; cohort
8.  Chronic kidney disease and risk of renal cell carcinoma: differences by race 
Background
The incidence of renal cell carcinoma in the United States differs by race/ethnicity. To better understand these disparities, we conducted a nested case-control study investigating renal cell carcinoma risk factors across racial/ethnic groups within the Kaiser Permanente Northern California health care network.
Methods
Our study included 3,136 renal cell carcinoma cases (2,152 white, 293 black, 425 Hispanic, 255 Asian) diagnosed between 1998 and 2008 and 31,031 individually matched controls (21,478 white, 2,836 black, 4,147 Hispanic, 2,484 Asian). Risk of renal cell carcinoma was assessed in relation to smoking status, body mass index (BMI), hypertension, and chronic kidney disease. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, and population attributable risk (PAR) to estimate by race the proportion of cases attributable to hypertension and chronic kidney disease.
Results
The association between chronic kidney disease and renal cell carcinoma differed markedly by race (Pinteraction<0.001), with associations observed among blacks (OR=10.4 [95% CI=6.0–17.9]), Asians (5.1 [2.2–11.7]), and Hispanics (2.3 [1.1–4.6]) but not whites (1.1 [0.6–1.9]). Hypertension, high BMI, and smoking were associated with renal cell carcinoma, but findings generally did not differ by race. Relative to other racial/ethnic groups, blacks had the highest proportion of renal cell carcinoma incidence attributable to hypertension and chronic kidney disease (combined, PAR=37%; hypertension only, PAR=27%; chronic kidney disease, PAR=10%).
Conclusions
Our findings suggest that hypertension and chronic kidney disease likely have contributed to the observed excess in renal cell carcinoma incidence among blacks compared with whites.
doi:10.1097/EDE.0000000000000205
PMCID: PMC4422505  PMID: 25393631
9.  Identifying gender differences in reported occupational information from three U.S. population-based case-control studies 
Objectives
Growing evidence suggests that gender-blind assessment of exposure may introduce exposure misclassification, but few studies have characterized gender differences across occupations and industries. We pooled control responses to job-, industry-, and exposure-specific questionnaires (modules) that asked detailed questions about work activities from three US population-based case-control studies to examine gender differences in work tasks and their frequencies.
Methods
We calculated the ratio of female to male controls that completed each module. For four job modules (assembly worker, machinist, health professional, janitor/cleaner) and for subgroups of jobs that completed those modules, we evaluated gender differences in task prevalence and frequency using Chi-square and Mann-Whitney U-tests, respectively.
Results
The 1,360 female and 2,245 male controls reported 6,033 and 12,083 jobs, respectively. Gender differences in female:male module completion ratios were observed for 39 of 45 modules completed by ≥20 controls. Gender differences in task prevalence varied in direction and magnitude. For example, female janitors were significantly more likely to polish furniture (79% vs. 44%), while male janitors were more likely to strip floors (73% vs. 50%). Women usually reported more time spent on tasks than men. For example, the median hours per week spent degreasing for production workers in product manufacturing industries was 6.3 for women and 3.0 for men.
Conclusions
Observed gender differences may reflect actual differences in tasks performed or differences in recall, reporting, or perception, all of which contribute to exposure misclassification and impact relative risk estimates. Our findings reinforce the need to capture subject-specific information on work tasks.
doi:10.1136/oemed-2013-101801
PMCID: PMC4177972  PMID: 24683012
gender; population-based studies; case-control studies; occupational exposure; occupational health
10.  Pooled analysis of mitochondrial DNA copy number and lung cancer risk in three prospective studies 
Background
We previously reported that higher levels of mitochondrial DNA copy number (mtDNA CN) were associated with lung cancer risk among male heavy smokers (i.e., ≥20 cigarettes per day) in the Alpha-Tocopherol Beta-Carotene (ATBC) study. Here, we present two additional prospective investigations nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and the Shanghai Women’s Health Study (SWHS), and pooled with previously published data from ATBC.
Materials
All DNA was extracted from peripheral whole blood samples using the phenol–chloroform method, and mtDNA CN was assayed by fluorescence-based quantitative polymerase chain reaction. Multivariate unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association of mtDNA CN and lung cancer risk.
Results
Overall, mtDNA CN was not associated with lung cancer risk in the PLCO, SWHS, or pooled populations (all P-trends > 0.42, P-heterogeneity = 0.0001), and mtDNA CN was inversely associated with lung cancer risk among male smokers in PLCO, the opposite direction observed in ATBC. Additionally, the mtDNA CN association observed among male heavy smokers in ATBC was the opposite direction in PLCO.
Conclusions
mtDNA CN was not consistently associated with lung cancer risk across three prospective study populations from Europe, Asia, and the US.
Impact
This pooled study suggests no consistent association between pre-diagnostic mtDNA CN levels and lung cancer risk across several populations.
doi:10.1158/1055-9965.EPI-14-1070
PMCID: PMC4257855  PMID: 25293879
Mitochondrial DNA copy number; lung cancer; cohorts; pooled; nested case-control
11.  Acculturation, sociodemographic and lifestyle factors associated with compliance with physical activity recommendations in the Mexican-American Mano A Mano cohort 
BMJ Open  2015;5(11):e008302.
Objectives
Being physically active is important for health, and few Mexican-Americans meet national US physical activity recommendations. The aim of this study was to investigate sociodemographic, acculturation and lifestyle factors that were associated with meeting physical activity recommendations in this group.
Design and setting
A cross-sectional analysis of a large population-based cohort study in southern Texas, USA.
Participants
Between 2001 and 2011, 21 551 adult members of the Mexican-American Mano A Mano cohort completed baseline questionnaires on physical activity and other lifestyle factors.
Outcomes
Meeting US physical activity recommendations was defined as participating in 150 min of moderate, or 75 min of vigorous, activity per week. Factors contributing to the likelihood of meeting physical activity recommendations were examined by sex and country of birth in multivariate logistic regression models.
Results
Less than half of all men and less than a quarter of all women met US physical activity recommendations. Having some college education, greater acculturation and current alcohol use were each associated with greater odds of meeting physical activity recommendations in all groups except US-born men. Higher body mass index was associated with lower odds of meeting recommendations in US-born and Mexico-born women.
Conclusions
Results demonstrate that factors associated with meeting physical activity recommendations differ by sex and country of birth. Tailored interventions to increase Mexican-Americans’ activity levels to achieve health benefits should consider education, acculturation and alcohol use.
doi:10.1136/bmjopen-2015-008302
PMCID: PMC4663445  PMID: 26608633
PUBLIC HEALTH; PREVENTIVE MEDICINE; EPIDEMIOLOGY
12.  Obesity and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: A Mendelian Randomization Study 
Background
Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE). However, the relationships may be affected by bias and confounding.
Methods
We used data from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.
Results
The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m2 increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.
Conclusions
People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
doi:10.1093/jnci/dju252
PMCID: PMC4200028  PMID: 25269698
13.  Occupational Exposure to Benzene and Non-Hodgkin Lymphoma in a Population-Based Cohort: The Shanghai Women’s Health Study 
Environmental Health Perspectives  2015;123(10):971-977.
Background
The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate as a result of inconsistent epidemiologic evidence. An International Agency for Research on Cancer (IARC) working group evaluated benzene in 2009 and noted evidence for a positive association between benzene exposure and NHL risk.
Objective
We evaluated the association between occupational benzene exposure and NHL among 73,087 women enrolled in the prospective population-based Shanghai Women’s Health Study.
Methods
Benzene exposure estimates were derived using a previously developed exposure assessment framework that combined ordinal job-exposure matrix intensity ratings with quantitative benzene exposure measurements from an inspection database of Shanghai factories collected between 1954 and 2000. Associations between benzene exposure metrics and NHL (n = 102 cases) were assessed using Cox proportional hazard models, with study follow-up occurring from December 1996 through December 2009.
Results
Women ever exposed to benzene had a significantly higher risk of NHL [hazard ratio (HR) = 1.87, 95% CI: 1.19, 2.96]. Compared with unexposed women, significant trends in NHL risk were observed for increasing years of benzene exposure (ptrend = 0.006) and increasing cumulative exposure levels (ptrend = 0.005), with the highest duration and cumulative exposure tertiles having a significantly higher association with NHL (HR = 2.07, 95% CI: 1.07, 4.01 and HR = 2.16, 95% CI: 1.17, 3.98, respectively).
Conclusions
Our findings, using a population-based prospective cohort of women with diverse occupational histories, provide additional evidence that occupational exposure to benzene is associated with NHL risk.
Citation
Bassig BA, Friesen MC, Vermeulen R, Shu XO, Purdue MP, Stewart PA, Xiang YB, Chow WH, Zheng T, Ji BT, Yang G, Linet MS, Hu W, Zhang H, Zheng W, Gao YT, Rothman N, Lan Q. 2015. Occupational exposure to benzene and non-Hodgkin lymphoma in a population-based cohort: the Shanghai Women’s Health Study. Environ Health Perspect 123:971–977; http://dx.doi.org/10.1289/ehp.1408307
doi:10.1289/ehp.1408307
PMCID: PMC4590744  PMID: 25748391
14.  Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization 
BACKGROUND & AIMS
Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE).
METHODS
We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett’s and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable.
RESULTS
Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62–0.79 for men and OR, 0.57; 95% CI 0.40–0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62–0.77 for men and OR, 0.61; 95% CI, 0.48–0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis.
CONCLUSIONS
Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.
doi:10.1016/j.cgh.2014.01.039
PMCID: PMC4130803  PMID: 24530603
Esophageal Cancer; Etiology; Risk Factors; Sex Differences
15.  Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium 
PLoS ONE  2015;10(9):e0138738.
Background
The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.
Methods
This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).
Results
Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.
Conclusion
Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
doi:10.1371/journal.pone.0138738
PMCID: PMC4583498  PMID: 26406593
16.  Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts 
Cancer research  2014;74(15):4090-4098.
We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex quantitative PCR assay. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis (OR(95% CI) by quartile: 1.00; 1.24(0.90–1.71); 1.27(0.91–1.78); and 1.86(1.33–2.62); P-trend=0.000022). Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length (OR(95% CI)) in the upper half of the fourth quartile were 2.41(1.28–4.52), 2.16(1.11–4.23) and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than six years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
doi:10.1158/0008-5472.CAN-14-0459
PMCID: PMC4119534  PMID: 24853549
Leukocytes; Lung cancer; Prospective; Telomeres
17.  Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study 
Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study, a cohort of 73,118 women ages 40 to 70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n=383, colon; n=236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73–1.59). However, among women with vitamin C intake below the median (83.9 mg/day) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15–5.18; p-trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously-formed NOCs increases risk of colorectal cancer.
doi:10.1002/ijc.28612
PMCID: PMC3980001  PMID: 24242755
18.  MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium 
PLoS ONE  2015;10(6):e0128617.
Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
doi:10.1371/journal.pone.0128617
PMCID: PMC4454432  PMID: 26039359
19.  Cholelithiasis and the risk of liver cancer: results from cohort studies of 134,546 Chinese men and women 
Background
Cholelithiasis and cholecystectomy have been proposed as risk factors for liver cancer, but findings have been inconsistent. We assessed this association using data from the Shanghai Women’s and Men’s Health Studies.
Methods
History of cholelithiasis and cholecystectomy were reported at baseline and follow-up interviews and liver cancer diagnoses were ascertained from the Shanghai Cancer Registry and Vital Statistics Unit. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated after adjustment for potential confounders.
Results
A history of cholelithiasis and cholecystectomy was reported by 9.5% and 3.6% of participants at baseline, respectively. After a total of 859,882 person-years of follow-up for women and 391,093 for men, incident liver cancer was detected in 160 women and 252 men. A positive association was observed between a history of cholelithiasis or cholecystectomy and liver cancer in men (aHR 1.46; 95% CI: 1.02, 2.07) and women (aHR 1.55; 95% CI: 1.06, 2.26). Similar results were observed for cholelithiasis only, but cholecystectomy did not reach statistical significance. There was no strong evidence for detection bias of liver cancer due to cholelithiasis or cholecystectomy.
Conclusion
Our study suggests that cholelithiasis and possibly cholecystectomy may increase the risk of liver cancer.
doi:10.1136/jech-2013-203503
PMCID: PMC4140434  PMID: 24574318
Medical subject heading key words;  China; cholecystectomy; cholelithiasis; cohort studies; gallstones; liver neoplasms
20.  Pathologic validation of renal cell carcinoma histology in the Surveillance, Epidemiology, and End Results program☆ 
Urologic oncology  2013;32(1):23.e9-23.13.
Purpose
The Surveillance, Epidemiology, and End Results (SEER) program is an important epidemiologic research tool to study cancer. No information is available on its pathologic accuracy for renal cell carcinoma (RCC).
Methods
Central pathology review was analyzed as a part of the United States Kidney Cancer Study. Cases previously identified through the Detroit SEER registry were reviewed. The sensitivity and specificity, and positive and negative predictive values were calculated for each SEER-assigned subtype, with the central review assignments used as the reference.
Results
Of the 498 cases included in this study, 490 (98.5%) were confirmed to be RCC. The overall agreement for histology was 78.2% (k = 0.55); however, individual cases were frequently reclassified. The sensitivity and specificity for SEER-assigned clear cell RCC were 79.1% and 88.1%, respectively, when based solely on the ICD-O-3 morphology code 8310 (n = 310), and 99.2% and 80.5% when 8312 (RCC not otherwise specified; n = 41) was also assumed to be clear cell. Although RCC not otherwise specified is frequently grouped with clear cell, only 78.1% had this histology. Assignments of papillary and chromophobe RCC had comparable sensitivities (73.5% and 72.4%, respectively) and specificities (97.5% and 97.6%). Positive predictive values for clear cell (excluding/including 8312), papillary, and chromophobe RCC were 95.5%/93.5%, 85.9%, and 65.6%, respectively.
Conclusions
Our findings confirm that nearly all RCC cases are correctly classified in SEER. The positive predictive value was higher for clear cell RCC than for papillary or chromophobe RCC, suggesting that pathologic confirmation may be warranted for studies of non–clear cell tumors. Published by Elsevier Inc.
doi:10.1016/j.urolonc.2012.08.011
PMCID: PMC4435970  PMID: 23453468
RCC; SEER; Histology; Pathology; Concordance; Accuracy
21.  A nested case–control study of leukocyte mitochondrial DNA copy number and renal cell carcinoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Carcinogenesis  2014;35(5):1028-1031.
Summary
This study reports the first prospective evidence that high leukocyte mtDNA copy number is associated with increased future risk of RCC, suggesting that oxidative DNA damage and mitochondrial dysfunction may contribute to renal carcinogenesis.
Mitochondrial DNA (mtDNA) is vulnerable to mutations, and the number of copies of mtDNA per cell may increase to compensate for DNA damage. Case–control studies have reported associations between altered mtDNA copy number and risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively. We conducted a nested case–control study (252 cases and 504 controls) of RCC risk in relation to pre-diagnostic leukocyte mtDNA copy number in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. mtDNA copy number was measured in triplicate using a fluorescence-based quantitative PCR assay; samples from 22 cases and 36 controls could not be assayed, leaving 230 cases and 468 controls for analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. High mtDNA copy number was associated with an increased risk of RCC, both overall (highest quartile versus lowest: OR = 2.0, 95% CI = 1.2–3.2; P trend = 0.002) and among cases diagnosed ≥6 years after blood collection (OR = 2.6, 95% CI = 1.4–5.0; P trend = 0.003). These findings did not differ significantly by sex, body mass index, history of hypertension or smoking status (P interaction ≥ 0.3). Results of this study suggest that high pre-diagnostic leukocyte mtDNA copy number, a suspected marker of oxidative DNA damage and mitochondrial dysfunction, is associated with increased future RCC risk.
doi:10.1093/carcin/bgt495
PMCID: PMC4004202  PMID: 24398668
22.  Common Variation at 1q24.1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer 
PLoS ONE  2015;10(3):e0122589.
So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.
doi:10.1371/journal.pone.0122589
PMCID: PMC4380462  PMID: 25826619
23.  Human metabolic correlates of body mass index 
Background
A high body mass index (BMI) is a major risk factor for several chronic diseases, but the biology underlying these associations is not well-understood. Dyslipidemia, inflammation, and elevated levels of growth factors and sex steroid hormones explain some of the increased disease risk, but other metabolic factors not yet identified may also play a role.
Design
In order to discover novel metabolic biomarkers of BMI, we used non-targeted metabolomics to assay 317 metabolites in blood samples from 947 participants and examined the cross-sectional associations between metabolite levels and BMI. Participants were from three studies in the United States and China. Height, weight, and potential confounders were ascertained by questionnaire (US studies) or direct measurement (Chinese study). Metabolite levels were measured using liquid-phase chromatography and gas chromatography coupled with mass spectrometry. We evaluated study-specific associations using linear regression, adjusted for age, gender, and smoking, and we estimated combined associations using random effects meta-analysis.
Results
The meta-analysis revealed 37 metabolites significantly associated with BMI, including 19 lipids, 12 amino acids, and 6 others, at the Bonferroni significance threshold (p<0.00016). Eighteen of these associations had not been previously reported, including histidine, an amino acid neurotransmitter, and butyrylcarnitine, a lipid marker of whole-body fatty acid oxidation. Heterogeneity by study was minimal (all Pheterogeneity >0.05). In total, 110 metabolites were associated with BMI at the p<0.05 level.
Conclusion
These findings establish a baseline for the BMI metabolome, and suggest new targets for researchers attempting to clarify mechanistic links between high BMIs and disease risk.
doi:10.1007/s11306-013-0574-1
PMCID: PMC4169991  PMID: 25254000
BMI; adiposity; metabolomics; epidemiology; obesity
24.  Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma 
Oncotarget  2015;6(6):4097-4109.
We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (Pmeta-analysis = 9.15 × 10−4, Pheterogeneity = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = −0.59, p = 5.61 × 10−6). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.
PMCID: PMC4414175  PMID: 25784652
RCC; GWAS; GSEA; eQTL
25.  Calibrating a population-based job-exposure matrix using inspection measurements to estimate historical occupational exposure to lead for a population-based cohort in Shanghai, China 
The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5,383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects’ jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20–50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79–0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in future epidemiologic analyses.
doi:10.1038/jes.2012.86
PMCID: PMC3508334  PMID: 22910004
lead; cancer; exposure assessment; occupational exposure; job exposure matrix; mixed-effects model

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