Publications by authors named "Neal D Freedman"

298 Publications

Association between Serum Ferritin, Incident Primary Liver Cancer, and Chronic Liver Disease Mortality in the Linxian Nutrition Intervention Trials: A Nested Case-Control Study.

J Gastroenterol Hepatol 2021 Jun 9. Epub 2021 Jun 9.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD).

Methods: We performed a nested case-control study in the Linxian Nutrition Intervention Trials (NIT). Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1,061 age-, gender- and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios (OR) and 95% confidence interval (CI). Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+) and trial.

Results: Participants with serum ferritin in highest quartile, as compared to those in lowest quartile, had an increased risk of CLD mortality (OR=1.72, 95% CI=1.12, 2.64, p-trend<0.01). Moreover, the association with higher serum ferritin was stronger among alcohol drinkers and those who were HCV+ (p-interaction<0.05). For incident liver cancer, risk estimates were above one but were not statistically significant.

Conclusion: In this study, higher levels of serum ferritin at baseline were associated with subsequent mortality from CLD, particularly if combined with alcohol drinking or viral hepatitis. Further work is warranted to confirm our findings.
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http://dx.doi.org/10.1111/jgh.15571DOI Listing
June 2021

Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.

Cancers (Basel) 2021 May 30;13(11). Epub 2021 May 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China.

Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma.

Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients.

Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.
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http://dx.doi.org/10.3390/cancers13112704DOI Listing
May 2021

ABO genotypes and the risk of esophageal and gastric cancers.

BMC Cancer 2021 May 22;21(1):589. Epub 2021 May 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr. 6E3280, Rockville, MD, 20850, USA.

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC).

Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer.

Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13).

Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.
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http://dx.doi.org/10.1186/s12885-021-08334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141232PMC
May 2021

Novel Biomarkers of Habitual Alcohol Intake and Associations with Risk of Pancreatic and Liver Cancers and Liver Disease Mortality.

J Natl Cancer Inst 2021 May 19. Epub 2021 May 19.

Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk.

Methods: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies.

Results: Two metabolites displayed a dose-response association with self-reported alcohol intake 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54; 95% CI = 1.51-4.27) and pancreatic cancer (OR = 1.43; 95% CI = 1.03-1.99) in EPIC and liver cancer (OR = 2.00; 95% CI = 1.44-2.77) and liver disease mortality (OR = 2.16; 95% CI = 1.63-2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19; 95% CI = 1.60-2.98) in ATBC.

Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
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http://dx.doi.org/10.1093/jnci/djab078DOI Listing
May 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
May 2021

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Science 2021 05 22;372(6543):725-729. Epub 2021 Apr 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
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http://dx.doi.org/10.1126/science.abg2365DOI Listing
May 2021

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts.

Cancer Res 2021 Apr 5;81(8):2246-2255. Epub 2021 Apr 5.

Division of Cancer Epidemiology and Genetics, National Institutes of Health, Rockville, Maryland.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137527PMC
April 2021

Serum Levels of Androgens, Estrogens, and Sex Hormone Binding Globulin and Risk of Primary Gastric Cancer in Chinese Men: A Nested Case-Control Study.

Cancer Prev Res (Phila) 2021 Mar 25. Epub 2021 Mar 25.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case-control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01-3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association. PREVENTION RELEVANCE: It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0497DOI Listing
March 2021

Concentrations of Cotinine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) in U.S. Non-Daily Cigarette Smokers.

Cancer Epidemiol Biomarkers Prev 2021 Jun 18;30(6):1165-1174. Epub 2021 Mar 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland.

Background: Accumulating evidence suggests that non-daily smokers have higher disease and mortality risks than never smokers. Yet, the accuracy of self-reported non-daily cigarette smoking is poorly understood.

Methods: We examined the concordance between self-reported non-daily smoking and serum cotinine in 18,835 adult participants (20 years or older) of the 2007 to 2014 National Health and Nutrition Examination Surveys, in comparison with daily smokers and nonsmokers. We also analyzed concentrations of the urinary biomarker 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by smoking status.

Results: In the study sample, 77.8% (14,660) reported currently not smoking (nonsmokers), 18.3% (3,446) smoked every day (daily smokers), and 3.9% (729) smoked on some days of the past month (non-daily smokers). Just 2.1% of nonsmokers had cotinine concentrations in the active smoking range (>10 ng/mL), compared with 70.4% of non-daily and 98.8% of daily smokers. Non-daily smokers reported smoking a median of 24 cigarettes per month [interquartile range (IQR) = 9-60] and had substantially higher concentrations of NNAL (median = 72.5; IQR = 14.8-211.0 pg/mL) than nonsmokers (median = 0.4; IQR = 0.4-2.1 pg/mL), although lower than daily smokers (median = 294.0; IQR = 148.0-542.0 pg/mL). Among non-daily smokers, concentrations of cotinine and NNAL were positively correlated with days and cigarettes smoked per month ( < 0.001).

Conclusions: We observed excellent concordance between self-reported non-daily cigarette smoking and concentrations of serum cotinine.

Impact: These results provide evidence for the validity of self-reported non-daily smoking and indicate that non-daily smokers are exposed to substantial concentrations of carcinogenic nitrosamines regardless of the low number of cigarettes they smoke per month.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172473PMC
June 2021

Tobacco Smoking and Risk of Second Primary Lung Cancer.

J Thorac Oncol 2021 Jun 17;16(6):968-979. Epub 2021 Mar 17.

Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California. Electronic address:

Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk.

Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.

Results: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (p < 0.001), 1.25 per 10 cigarettes per day (p < 0.001), and 1.99 (p < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001).

Conclusions: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.
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http://dx.doi.org/10.1016/j.jtho.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159872PMC
June 2021

Coffee consumption and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study.

Int J Epidemiol 2021 Feb 24. Epub 2021 Feb 24.

Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch, National Cancer Institute, Rockville, MD, USA.

Background: Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort.

Methods: Coffee intake was assessed at baseline in the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers.

Results: We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of <1, 1, 2-3 and ≥4 cups/day, respectively (Ptrend = 0.00003). This relationship was observed among never-smokers (≥4 cups/day: HR 0.62, 95% CI 0.46, 0.83; Ptrend = 0.000003) but not ever-smokers (HR 0.85, 95% CI 0.70, 1.05; Ptrend = 0.35; Pinteraction = 0.0009) and remained in analyses restricted to cases diagnosed >10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74).

Conclusion: In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective.
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http://dx.doi.org/10.1093/ije/dyab011DOI Listing
February 2021

Gastroesophageal reflux disease: A risk factor for laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma in the NIH-AARP Diet and Health Study cohort.

Cancer 2021 Jun 22;127(11):1871-1879. Epub 2021 Feb 22.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: Prior studies have suggested that gastroesophageal reflux disease (GERD) may be associated with risk of squamous cancers of the larynx and esophagus; however, most of these studies have had methodological limitations or insufficient control for potential confounders.

Methods: We prospectively examined the association between GERD and esophageal adenocarcinoma (EADC), esophageal squamous cell carcinoma (ESCC), and laryngeal squamous cell carcinoma (LSCC) in 490,605 participants of the NIH-AARP Diet and Health Study cohort who were 50-71 years of age at baseline. Exposure to risk factors were obtained from the baseline questionnaire. GERD diagnosis was extracted among eligible participants via linkage to Medicare diagnoses codes and then multiply imputed for non-Medicare-eligible participants. Hazard ratios (HRs) and 95% CIs of GERD were computed using Cox regression.

Results: From 1995 to 2011, we accrued 931 cases of EADC, 876 cases of LSCC, and 301 cases of ESCC in this cohort and estimated multivariable-adjusted HRs of 2.23 (95% CI, 1.72-2.90), 1.91 (95% CI, 1.24-2.94), and 1.99 (95% CI, 1.39-2.84) for EADC, LSCC, and ESCC, respectively. The associations were independent of sex, smoking status, alcohol intake, and follow-up time periods. We estimated that among the general population in the United States, 22.04% of people aged 50-71 years suffered from GERD. Using risk factor distributions for the United States from national survey data, 16.92% of LSCC cases and 17.32% of ESCC cases among individuals aged 50-71 years were estimated to be associated with GERD.

Conclusion: GERD is a common gastrointestinal disorder, but future prospective studies are needed to replicate our findings. If replicated, they may inform clinical surveillance of GERD patients and suggest new avenues for prevention of these malignancies.
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http://dx.doi.org/10.1002/cncr.33427DOI Listing
June 2021

Associations of coffee and tea consumption with lung cancer risk.

Int J Cancer 2020 Dec 16. Epub 2020 Dec 16.

Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, South Korea.

Associations of coffee and tea consumption with lung cancer risk have been inconsistent, and most lung cancer cases investigated were smokers. Included in this study were over 1.1 million participants from 17 prospective cohorts. Cox regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential effect modifications by sex, smoking, race, cancer subtype and coffee type were assessed. After a median 8.6 years of follow-up, 20 280 incident lung cancer cases were identified. Compared with noncoffee and nontea consumption, HRs (95% CIs) associated with exclusive coffee drinkers (≥2 cups/d) among current, former and never smokers were 1.30 (1.15-1.47), 1.49 (1.27-1.74) and 1.35 (1.15-1.58), respectively. Corresponding HRs for exclusive tea drinkers (≥2 cups/d) were 1.16 (1.02-1.32), 1.10 (0.92-1.32) and 1.37 (1.17-1.61). In general, the coffee and tea associations did not differ significantly by sex, race or histologic subtype. Our findings suggest that higher consumption of coffee or tea is associated with increased lung cancer risk. However, these findings should not be assumed to be causal because of the likelihood of residual confounding by smoking, including passive smoking, and change of coffee and tea consumption after study enrolment.
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http://dx.doi.org/10.1002/ijc.33445DOI Listing
December 2020

Impact of Population Growth and Aging on Estimates of Excess U.S. Deaths During the COVID-19 Pandemic, March to August 2020.

Ann Intern Med 2021 04 15;174(4):437-443. Epub 2020 Dec 15.

National Cancer Institute, Rockville, Maryland (M.S.S., J.S.A., M.G., P.S.A., N.D.F., A.B.D.).

Background: Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, especially increases in the population older than 65 years.

Objective: To estimate excess deaths in the United States in 2020, after accounting for population changes.

Design: Surveillance study.

Setting: United States, March to August 2020.

Participants: All decedents.

Measurements: Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age.

Results: From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non-COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non-COVID-19 deaths). Most excess non-COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non-COVID-19 excess deaths.

Limitation: Provisional death data are underestimated because of reporting delays.

Conclusion: The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non-COVID-19 death estimates, providing important information for guiding future clinical and public health interventions.

Primary Funding Source: National Cancer Institute.
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http://dx.doi.org/10.7326/M20-7385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901655PMC
April 2021

White Blood Cell Count and Risk of Incident Lung Cancer in the UK Biobank.

JNCI Cancer Spectr 2020 Apr 12;4(2):pkz102. Epub 2019 Dec 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK).

Methods: We evaluated 424 407 adults aged 37-73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006-2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference.

Results: There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HR = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers ( /  = 244 / 19 464, HR = 2.15, 95% CI = 1.46 to 3.16), former smokers ( /  = 280 / 69 198, HR = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (n / n = 108 / 111 294, HR = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (n /  = 329 / 22 934, HR = 2.95, 95% CI = 2.04 to 4.26) and former smokers ( /  = 358/71 616, HR = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions.

Conclusions: Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men.
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http://dx.doi.org/10.1093/jncics/pkz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083262PMC
April 2020

Using whole-exome sequencing and protein interaction networks to prioritize candidate genes for germline cutaneous melanoma susceptibility.

Sci Rep 2020 10 14;10(1):17198. Epub 2020 Oct 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Using a network propagation method, we ranked candidate genes by their similarity to known disease genes in protein-protein interaction networks and identified gene clusters with functional connectivity. Using this approach, we identified several new candidate susceptibility genes that warrant future investigations such as NGLY1, IL1RN, FABP2, PRKDC, and PROSER2. The propagated network analysis also allowed us to link families that did not have common underlying genes but that carried variants in genes that interact on protein-protein interaction networks. In conclusion, our study provided an analysis perspective for gene prioritization in the context of genetic heterogeneity across families and prioritized top potential candidate susceptibility genes in our dataset.
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http://dx.doi.org/10.1038/s41598-020-74293-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560829PMC
October 2020

Demographic Characteristics, Cigarette Smoking, and e-Cigarette Use Among US Adults.

JAMA Netw Open 2020 10 1;3(10):e2020694. Epub 2020 Oct 1.

Metabolic Epidemiology Branch, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.20694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094416PMC
October 2020

Associations between Helicobacter pylori with nonalcoholic fatty liver disease and other metabolic conditions in Guatemala.

Helicobacter 2020 Dec 2;25(6):e12756. Epub 2020 Oct 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Previous studies have suggested an association between Helicobacter pylori (H pylori) and nonalcoholic fatty liver disease (NAFLD). The aim of the current study was to examine the association in Guatemala, a region with elevated prevalences of both H pylori and NAFLD. Associations between H pylori and other metabolic conditions were also examined, as were associations between H hepaticus and H bilis and the metabolic conditions.

Materials & Methods: The analysis included 424 participants from a cross-sectional study in Guatemala. H pylori seropositivity was defined as positivity for ≥ 4 antigens. Seropositivities for H bilis and H hepaticus were defined as positivity for ≥ 2 antigens. NAFLD was estimated using the Fatty Liver Index and the Hepatic Steatosis Index. Other conditions examined were obesity, central obesity, hypercholesterolemia, low HDL, diabetes and metabolic syndrome (MetSyn). Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were estimated.

Results: No overall associations between H pylori,H hepaticus, or H bilis and NAFLD or related metabolic conditions were found. Seropositivity for H pylori antigens CagA and VacA and H hepaticus antigen HH0713 was each significantly associated with NAFLD, however. In addition, associations were observed between the H pylori antigens HyuA, HP1564, and UreA and specified metabolic conditions.

Conclusions: While no overall associations between H pylori or Helicobacter species with NAFLD or related conditions were observed, some selected Helicobacter spp. antigens were associated with NAFLD. Further research is warranted to examine whether H. species are associated with any metabolic condition.
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http://dx.doi.org/10.1111/hel.12756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688101PMC
December 2020

Serum Concentrations of Per- and Polyfluoroalkyl Substances and Risk of Renal Cell Carcinoma.

J Natl Cancer Inst 2021 May;113(5):580-587

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.

Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.

Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.

Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.
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http://dx.doi.org/10.1093/jnci/djaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096365PMC
May 2021

Aspirin use and ovarian cancer risk using extended follow-up of the PLCO Cancer Screening Trial.

Gynecol Oncol 2020 11 10;159(2):522-526. Epub 2020 Sep 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD 20850, USA.

Objective: Frequent use of aspirin has been associated with reduced ovarian cancer risk in observational studies, but it is unclear if only daily, low-dose aspirin confers a protective benefit. We examined associations between patterns of aspirin use and ovarian cancer risk among postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

Methods: Participants were enrolled in PLCO between 1993 and 2001 and followed for cancer outcomes through 2014. Detailed data on aspirin use (e.g., dose, frequency and duration) were ascertained via the supplemental questionnaire (SQX) administered in 2006-2007. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between aspirin use (defined as use ≥once/week) and incident ovarian cancer. We conducted analyses among all women in the study sample and stratified by age at the time of the SQX.

Results: There were 41,633 women included in this analysis, of whom 223 developed incident ovarian cancer. Overall, aspirin use was not significantly associated with ovarian cancer risk (HR: 0.93, 95% CI: 0.72-1.21). Among women <70 years, there was suggestion of an inverse association for daily use of aspirin (HR: 0.65, 95% CI: 0.40-1.05), low-dose aspirin (HR: 0.79, 95% CI: 0.51-1.24) and daily use of low-dose aspirin (HR: 0.64, 95% CI: 0.38-1.09).

Conclusions: These findings suggest a potential modest effect of daily, low-dose aspirin in reducing ovarian cancer risk. However, effect estimates were imprecise given the small number of events, and further research will be needed to confirm and extend these findings.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584756PMC
November 2020

Aspirin use and ovarian cancer risk using extended follow-up of the PLCO Cancer Screening Trial.

Gynecol Oncol 2020 11 10;159(2):522-526. Epub 2020 Sep 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD 20850, USA.

Objective: Frequent use of aspirin has been associated with reduced ovarian cancer risk in observational studies, but it is unclear if only daily, low-dose aspirin confers a protective benefit. We examined associations between patterns of aspirin use and ovarian cancer risk among postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

Methods: Participants were enrolled in PLCO between 1993 and 2001 and followed for cancer outcomes through 2014. Detailed data on aspirin use (e.g., dose, frequency and duration) were ascertained via the supplemental questionnaire (SQX) administered in 2006-2007. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between aspirin use (defined as use ≥once/week) and incident ovarian cancer. We conducted analyses among all women in the study sample and stratified by age at the time of the SQX.

Results: There were 41,633 women included in this analysis, of whom 223 developed incident ovarian cancer. Overall, aspirin use was not significantly associated with ovarian cancer risk (HR: 0.93, 95% CI: 0.72-1.21). Among women <70 years, there was suggestion of an inverse association for daily use of aspirin (HR: 0.65, 95% CI: 0.40-1.05), low-dose aspirin (HR: 0.79, 95% CI: 0.51-1.24) and daily use of low-dose aspirin (HR: 0.64, 95% CI: 0.38-1.09).

Conclusions: These findings suggest a potential modest effect of daily, low-dose aspirin in reducing ovarian cancer risk. However, effect estimates were imprecise given the small number of events, and further research will be needed to confirm and extend these findings.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584756PMC
November 2020

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PLoS One 2020 3;15(9):e0237792. Epub 2020 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470401PMC
October 2020

Independent and Joint Associations between Serum Calcium, 25-Hydroxy Vitamin D, and the Risk of Primary Liver Cancer: A Prospective Nested Case-Control Study.

Cancer Epidemiol Biomarkers Prev 2020 10 20;29(10):2057-2064. Epub 2020 Aug 20.

Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Accumulating evidence has shown that serum calcium and vitamin D may be associated with or influence various cancer risks. However, no prospective studies have evaluated the independent and joint associations between prediagnostic levels of serum calcium and vitamin D and future risk of incident primary liver cancer.

Methods: We used a nested case-control design to evaluate subjects over 22 years of follow-up. Serum calcium, 25-hydroxy vitamin D [25(OH)D], and three markers of hepatitis B virus and hepatitis C virus were measured in baseline serum from 226 incident primary liver cancer cases and 1,061 matched controls. We calculated ORs and 95% confidence intervals (CI) using logistic regression to estimate the associations between calcium, 25(OH)D, and primary liver cancer risk.

Results: Multivariable adjusted models showed that subjects with both low (OR = 1.48, 95% CI = 1.01-2.17) or high (OR = 1.92, 95% CI = 1.34-2.76) calcium had an increased primary liver cancer risk, while those with high 25(OH)D had a decreased risk of primary liver cancer (OR = 0.54, 95% CI = 0.35-0.82). In joint analyses, when compared with subjects with medium calcium and 25(OH)D, subjects with high calcium and medium 25(OH)D had elevated odds of developing primary liver cancer (OR = 1.89, 95% CI = 1.17-3.05); those with medium calcium and high 25(OH)D had reduced odds of developing primary liver cancer (OR = 0.34, 95% CI = 0.17-0.67); and subjects in other classifications of calcium and serum 25(OH)D levels had no change in the odds of developing primary liver cancer (all > 0.05).

Conclusions: In a nutrient-deficient population, we found that serum calcium and serum 25(OH)D could potentially be modifiable risk or protective factors.

Impact: Our findings provide potential targets for primary liver cancer prevention and control.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0417DOI Listing
October 2020

Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality.

Am J Hum Genet 2020 09 5;107(3):418-431. Epub 2020 Aug 5.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry (i.e., middle age for most participants). The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477009PMC
September 2020

Aflatoxin B exposure and liver cirrhosis in Guatemala: a case-control study.

BMJ Open Gastroenterol 2020 07;7(1)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Objective: In Guatemala, cirrhosis is among the 10 leading causes of death, and mortality rates have increased lately. The reasons for this heavy burden of disease are not clear as the prevalence of prominent risk factors, such as hepatitis B virus, hepatitis C virus and heavy alcohol consumption, appears to be low. Aflatoxin B (AFB) exposure, however, appears to be high, and thus could be associated with the high burden of cirrhosis. Whether AFB increases the risk of cirrhosis in the absence of viral infection, however, is not clear.

Design: Cirrhosis cases (n=100) from two major referral hospitals in Guatemala City were compared with controls (n=200) from a cross-sectional study. Logistic regression was used to estimate the ORs and 95% CIs of cirrhosis and quintiles of AFB in crude and adjusted models. A sex-stratified analysis was also conducted.

Results: The median AFB level was significantly higher among the cases (11.4 pg/mg) than controls (5.11 pg/mg). In logistic regression analyses, higher levels of AFB was associated with cirrhosis (quintile 5 vs quintile 1, OR: 11.55; 95% CI 4.05 to 32.89). No attenuation was observed with adjustment by sex, ethnicity, hepatitis B virus status, and heavy alcohol consumption. A significantly increasing trend in association was observed in both models (p trend <0.01). Additionally, the cirrhosis-AFB association was more prominent among men.

Conclusions: The current study found a significant positive association between AFB exposure and cirrhosis. Mitigation of AFB exposure and a better understanding of additional risk factors may be important to reduce the burden of cirrhosis in Guatemala.
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http://dx.doi.org/10.1136/bmjgast-2020-000380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342465PMC
July 2020

Whole grain and dietary fiber intake and risk of colorectal cancer in the NIH-AARP Diet and Health Study cohort.

Am J Clin Nutr 2020 09;112(3):603-612

Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Whole grains and other foods containing fiber are thought to be inversely related to colorectal cancer (CRC). However, whether these associations reflect fiber or fiber source remains unclear.

Objectives: We evaluated associations of whole grain and dietary fiber intake with CRC risk in the large NIH-AARP Diet and Health Study.

Methods: We used Cox proportional hazard models to estimate HRs and 95% CIs for whole grain and dietary fiber intake and risk of CRC among 478,994 US adults, aged 50-71 y. Diet was assessed using a self-administered FFQ at baseline in 1995-1996, and 10,200 incident CRC cases occurred over 16 y and 6,464,527 person-years of follow-up. We used 24-h dietary recall data, collected on a subset of participants, to evaluate the impact of measurement error on risk estimates.

Results: After multivariable adjustment for potential confounders, including folate, we observed an inverse association for intake of whole grains (HRQ5 vs.Q1 : 0.84; 95% CI: 0.79, 0.90; P-trend < 0.001), but not dietary fiber (HRQ5 vs. Q1: 0.96; 95% CI: 0.88, 1.04; P-trend = 0.40), with CRC incidence. Intake of whole grains was inversely associated with all CRC cancer subsites, particularly rectal cancer (HRQ5 vs. Q1: 0.76; 95% CI: 0.67, 0.87; P-trend < 0.001). Fiber from grains, but not other sources, was associated with lower incidence of CRC (HRQ5 vs. Q1: 0.89; 95% CI: 0.83, 0.96; P-trend < 0.001), particularly distal colon (HRQ5 vs. Q1: 0.84; 95% CI: 0.73, 0.96; P-trend = 0.005) and rectal cancer (HRQ5 vs. Q1: 0.77; 95% CI: 0.66, 0.88; P-trend < 0.001).

Conclusions: Dietary guidance for CRC prevention should focus on intake of whole grains as a source of fiber.
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http://dx.doi.org/10.1093/ajcn/nqaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458778PMC
September 2020

Seropositivity for Helicobacter pylori and hepatobiliary cancers in the PLCO study.

Br J Cancer 2020 09 29;123(6):909-911. Epub 2020 Jun 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Helicobacter has been suggested to play a possible role in hepatitis, gallstones, and hepatobiliary tumours. We assessed whether seropositivity to 15 H. pylori proteins was associated with subsequent incidence of 74 biliary tract and 105 liver cancer cases vs. 357 matched controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Odds ratios and 95% confidence intervals were computed by conditional logistic regression after adjustment for known hepatobiliary cancer risk factors. H. pylori seropositivity was not associated with either biliary tract (1.76, 0.90-3.46) or liver cancer (0.87, 0.46-1.65). CagA seropositivity was associated with both endpoints, although the latter association was not statistically significant (biliary tract: 2.16, 1.03-4.50; liver cancer: 1.96, 0.98-3.93) and neither association was statistically significant after correcting for multiple comparisons. Together, these results suggest possible associations between H. pylori and hepatobiliary cancer and suggest the value of future studies investigating the association.Trial registration number: NCT00339495.
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http://dx.doi.org/10.1038/s41416-020-0961-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493958PMC
September 2020

Quantifying the association of low-intensity and late initiation of tobacco smoking with total and cause-specific mortality in Asia.

Tob Control 2021 05 16;30(3):328-335. Epub 2020 Jun 16.

Division of Epidemiology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Background: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts.

Methods: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis.

Findings: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence.

Conclusions: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.
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http://dx.doi.org/10.1136/tobaccocontrol-2019-055412DOI Listing
May 2021

Dose-Response Association of Low-Intensity and Nondaily Smoking With Mortality in the United States.

JAMA Netw Open 2020 06 1;3(6):e206436. Epub 2020 Jun 1.

Metabolic Epidemiology Branch, Division of Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Importance: An increasing proportion of US smokers smoke at low intensity and not every day. Some nondaily smokers have always had this pattern, whereas others previously smoked daily. The effect of reducing the level of smoking from daily to nondaily smoking and the dose response at low smoking levels are poorly understood.

Objective: To evaluate risk of all-cause and cause-specific mortality among nondaily and daily cigarette smokers, by cigarettes per month, years after reducing from daily to nondaily smoking, and years since quitting.

Design, Setting, And Participants: A prospective cohort study using harmonized data from multiple cycles of the Tobacco Use Supplements to the Current Population Survey (TUS-CPS), linked to the National Death Index, were analyzed during the period from 2018 to 2020. Adults completed the 1992-1993, 1995-1996, 1998-1999, 2000, 2001-2002, 2003, 2006-2007, or 2010-2011 TUS-CPS. Cigarette smokers were classified as daily or nondaily users; current nondaily smokers were further categorized by whether they previously smoked every day.

Main Outcomes And Measures: Hazard ratios (HRs) and 95% CIs for risks of mortality vs never smoking. Age was the underlying time metric, adjusted for sex, race/ethnicity, education, survey year, and household income.

Results: Among 505 500 participants (aged 18-103 years), approximately 47 000 deaths occurred. The median number of cigarettes smoked per month was 600 (interquartile range, 300-600) (20 cigarettes per day [interquartile range, 10-20 cigarettes per day]) for daily cigarette smokers and 40 (interquartile range, 15-90) for lifelong nondaily smokers. Nevertheless, both current daily (HR, 2.32; 95% CI, 2.25-2.38) and lifelong nondaily (HR, 1.82; 95% CI, 1.65-2.01) smokers had higher all-cause mortality risks than never smokers. Associations were observed for 6 to 10 cigarettes per month and increased with greater-intensity use. Nondaily smokers who previously smoked every day had lower mortality risks than daily smokers, with similar HRs after 10 or more years of nondaily smoking as lifelong nondaily smokers (HR vs never smokers, 1.73; 95% CI, 1.56-1.92). Yet, their risks were higher than former smokers who quit 10 or more years before (HR vs never smokers, 1.18; 95% CI, 1.15-1.22).

Conclusions And Relevance: Although reducing smoking from daily to nondaily was associated with decreased mortality risk, cessation was associated with far greater benefit. Lifelong nondaily smokers have higher mortality risks than never smokers, even among those smoking 6 to 10 cigarettes per month. Thus, all smokers should quit, regardless of how infrequently they smoke.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272118PMC
June 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020