Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-16 (of 16 Records) |
Query Trace: Freedman ND[original query] |
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Smoke exposure associated with higher urinary benzene biomarker muconic acid (MUCA) in golestan cohort study participants
Bhandari D , Zhu Y , Zhang C , Zhu W , Alexandridis A , Etemadi A , Freedman ND , Chang C , Abnet CC , Dawsey SM , Inoue-Choi M , Poustchi H , Pourshams A , Boffetta P , Malekzadeh R , Blount B . Biomarkers 2023 28 (7) 1-9 Background. Benzene is a known human carcinogen. Human exposure to benzene can be assessed by measuring trans, trans-muconic acid (MUCA) in urine. Golestan Province in northeastern Iran has been reported to have high incidence of esophageal cancer linked to the use of tobacco products. This manuscript evaluates the urinary MUCA concentrations among the participants of the Golestan Cohort Study (GCS).Methods. We analyzed MUCA concentration in 177 GCS participants' urine samples and performed nonparametric pairwise multiple comparisons to determine statistically significant difference among six different product use groups. Mixed effects model was fitted on 22 participants who exclusively smoked cigarette and 51 participants who were classified as nonusers. The urinary MUCA data were collected at the baseline and approximately five years later, and intraclass correlation coefficient (ICC) was calculated from the model.Results. Compared with nonusers, tobacco smoking was associated with higher urinary MUCA concentrations. Based on the nonparametric test of pairwise multiple comparisons, MUCA concentrations among participants who smoked combusted tobacco products were statistically significantly higher compared to nonusers. Urinary MUCA collected five years apart from the same individuals showed moderate reliability (ICC = 0.41), which was expected given the relatively short half-life (∼6 hrs) of MUCA.Conclusion. Our study revealed that tobacco smoke was positively associated with increased levels of urinary MUCA concentration, indicating that it is a significant source of benzene exposure among GCS participants. |
Exposure to polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines and incidence of esophageal cancer
Etemadi A , Poustchi H , Chang CM , Calafat AM , Blount BC , Bhandari D , Wang L , Roshandel G , Alexandridis A , Botelho JC , Xia B , Wang Y , Sosnoff CS , Feng J , Nalini M , Khoshnia M , Pourshams A , Sotoudeh M , Gail MH , Dawsey SM , Kamangar F , Boffetta P , Brennan P , Abnet CC , Malekzadeh R , Freedman ND . J Natl Cancer Inst 2023 BACKGROUND: Studying carcinogens in tobacco and non-tobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. METHODS: Golestan Cohort Study (GCS) has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma (ESCC). For this nested study, the cases comprised of all incident cases by Jan 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and tobacco-specific nitrosamines (TSNAs). We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for associations between the 90th versus the 10th percentiles of the biomarker concentrations and incident ESCC. RESULTS: Among individuals who did not currently use tobacco (148 cases/163 controls), two acrolein metabolites, two acrylonitrile metabolites, one propylene oxide metabolite and one 1,3-butadiene metabolite were significantly associated with incident ESCC (adjusted ORs between 1.8 and 4.3). Among tobacco users (57 cases/63 controls), metabolites of two other VOCs (styrene and xylene) were associated with ESCC (ORs= 6.2 and 9.0). In tobacco users, two TSNAs (NNN and N'-Nitrosoanatabine) were also associated with ESCC. Suggestive associations were seen with some PAHs (especially 2-hydroxynaphthalene) in non-users of tobacco products and other TSNAs in tobacco users. CONCLUSION: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications. |
COVID-19 SeroHub, an online repository of SARS-CoV-2 seroprevalence studies in the United States.
Freedman ND , Brown L , Newman LM , Jones JM , Benoit TJ , Averhoff F , Bu X , Bayrak K , Lu A , Coffey B , Jackson L , Chanock SJ , Kerlavage AR . Sci Data 2022 9 (1) 727 Seroprevalence studies provide useful information about the proportion of the population either vaccinated against SARS-CoV-2, previously infected with the virus, or both. Numerous studies have been conducted in the United States, but differ substantially by dates of enrollment, target population, geographic location, age distribution, and assays used. This can make it challenging to identify and synthesize available seroprevalence data by geographic region or to compare infection-induced versus combined infection- and vaccination-induced seroprevalence. To facilitate public access and understanding, the National Institutes of Health and the Centers for Disease Control and Prevention developed the COVID-19 Seroprevalence Studies Hub (COVID-19 SeroHub, https://covid19serohub.nih.gov/ ), a data repository in which seroprevalence studies are systematically identified, extracted using a standard format, and summarized through an interactive interface. Within COVID-19 SeroHub, users can explore and download data from 178 studies as of September 1, 2022. Tools allow users to filter results and visualize trends over time, geography, population, age, and antigen target. Because COVID-19 remains an ongoing pandemic, we will continue to identify and include future studies. |
Urinary nitrate and sodium in a high-risk area for upper gastrointestinal cancers: Golestan Cohort Study
Etemadi A , Buller ID , Hashemian M , Roshandel G , Poustchi H , Espinosa MM , Blount BC , Pfeiffer CM , Keshavarzi B , Flory AR , Nasseri-Moghaddam S , Dawsey SM , Freedman ND , Abnet CC , Malekzadeh R , Ward MH . Environ Res 2022 214 113906 BACKGROUND: The epidemiological evidence regarding the carcinogenicity of nitrate and sodium in drinking water is limited, partly because measuring the exposure at the individual level is complex. Most studies have used nitrate in water supplies as a proxy for individual exposure, but dietary intakes and other factors may contribute to the exposure. The present study investigates the factors associated with urinary nitrate and sodium in a high-risk area for esophageal and gastric cancers. METHODS: For this cross-sectional study, we used data and samples collected in 2004-2008 during the enrollment phase of the Golestan Cohort Study from a random sample of 349 participants (300 individuals from 24 rural villages and 49 from the city of Gonbad), stratified by average water nitrate in their district, the source of drinking water, and the usual dietary intake of nitrate and sodium. Nitrate, sodium, and creatinine were measured in a spot urine sample collected at the time of interview. We used the provincial cancer registry data to calculate the cumulative incidence rates of esophageal and gastric cancers for each location through June 1, 2020, and used weighted partial Pearson correlation to compare the incidence rates with median urinary nitrate and sodium in each village or the city. RESULTS: Among 349 participants (mean age±SD: 50.7 ± 8.6 years), about half (n = 170) used groundwater for drinking, and the use of ground water was significantly more common in high-elevation locations (75.8%). The geometric mean of the creatinine-corrected urinary nitrate concentration was 68.3 mg/g cr (95%CI: 64.6,72.3), and the corresponding geometric mean for urinary sodium was 150.0 mmoL/g cr (95%CI: 139.6161.1). After adjusting for confounders, urinary nitrate was associated with being a woman, drinking groundwater, and living in high-elevation locations, but not with estimated dietary intake. Urinary sodium concentration was significantly associated with monthly precipitation at the time of sampling but not with elevation or drinking water source. There were significant positive correlations between both median urinary nitrate and sodium in each location and esophageal cancer incidence rates adjusted for sex and age (r = 0.65 and r = 0.58, respectively, p < 0.01), but not with gastric cancer incidence. CONCLUSION: In a rural population at high risk for esophageal and gastric cancers, nitrate excretion was associated with living at a higher elevation and using groundwater for drinking. The associations between nitrate and sodium excretion with esophageal cancer incidence warrant future investigation. |
Lead poisoning among asymptomatic individuals with a long-term history of opiate use in Golestan Cohort Study
Etemadi A , Hariri S , Hassanian-Moghaddam H , Poustchi H , Roshandel G , Shayanrad A , Kamangar F , Boffetta P , Brennan P , Dargan PI , Dawsey SM , Jones RL , Freedman ND , Malekzadeh R , Abnet CC . Int J Drug Policy 2022 104 103695 BACKGROUND: Recent reports of lead poisoning suggest that people who use opium may be exposed to high amounts of lead. Here, we investigate the association between opium use and blood lead levels (BLL) in a population-based cohort study. METHODS: In 2017, we studied a random sample of 410 people who currently (both within the past year and the past month) used opium and 104 who did not from participants of the Golestan Cohort Study in northeast Iran. Participants were stratified by sex and tobacco use history, completed a comprehensive opiate and tobacco use questionnaire and provided blood. BLL was measured by Lead Care® II Blood Lead Test Kit, validated by inductively coupled plasma triple quadrupole mass spectrometry. BLL was categorized as "<5 µg/dL", "elevated" (5-10 µg/dL), "high" (10-50 µg/dL), and "very high" (above 50 µg/dL). To assess the association between BLL categories and opiate use, route of consumption and weekly use, we used ordered logistic regression models, and report OR (odds ratio) and 95% CI (confidence interval) adjusted for age, sex, place of residence, education, occupation, household fuel type, and tobacco use. RESULTS: In the cohort, participants used only raw (teriak) or refined (shireh) opium, which were smoked (45%, n = 184), taken orally (46%, n = 189), or both (9%, n = 37), for a mean duration of 24.2 (standard deviation: 11.6) years. The median BLL was significantly higher in people who currently used opium (11.4 µg/dL; IQR: 5.2-23.4) compared with those who did not (2.3 µg/dL; IQR: 2.3-4.2), and the highest median BLL was seen in oral use (21.7 µg/dL; IQR: 12.1-34.1). The BLL was <5 µg/dL among 79.8% of people with no opiate use, compared with only 22.7% in those using opium. BLL was elevated in 21.7%, high in 50.5% and very high in 5.1% of people using opium. About 95% of those with oral (180/189) or dual use (35/37) and 55% (102/184) of those who smoked opium had levels of blood lead above 5 µg/dL. The OR for the association between any opium use and each unit of increase in BLL category was 10.5 (95%CI: 5.8-19.1), and oral use of opium was a very strong predictor of increasing BLL category (OR=74.1; 95%CI: 35.1-156.3). This odds ratio was 38.8 (95%CI: 15.9-95.1) for dual use and 4.9 (95%CI: 2.6-9.1) for opium smoking. There was an independent dose-response association between average weekly dose and BLL among people using opium, overall and when stratified by route of use. CONCLUSION: Our results indicate that regular use of lead-adulterated opium can expose individuals to high levels of lead, which may contribute to mortality and cancer risks associated with long-term opium use. |
Associations between Biomarkers of Exposure and Lung Cancer Risk among Exclusive Cigarette Smokers in the Golestan Cohort Study.
Rostron BL , Wang J , Etemadi A , Thakur S , Chang JT , Bhandari D , Botelho JC , De Jesús VR , Feng J , Gail MH , Inoue-Choi M , Malekzadeh R , Pourshams A , Poustchi H , Roshandel G , Shiels MS , Wang Q , Wang Y , Xia B , Boffetta P , Brennan P , Abnet CC , Calafat AM , Wang L , Blount BC , Freedman ND , Chang CM . Int J Environ Res Public Health 2021 18 (14) Biomarkers of tobacco exposure are known to be associated with disease risk but previous studies are limited in number and restricted to certain regions. We conducted a nested case–control study examining baseline levels and subsequent lung cancer incidence among current male exclusive cigarette smokers in the Golestan Cohort Study in Iran. We calculated geometric mean biomarker concentrations for 28 matched cases and 52 controls for the correlation of biomarker levels among controls and for adjusted odds’ ratios (ORs) for lung cancer incidence by biomarker concentration, accounting for demographic characteristics, smoking quantity and duration, and opium use. Lung cancer cases had higher average levels of most biomarkers including total nicotine equivalents (TNE-2), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and 3-hydroxyfluorene (3-FLU). Many biomarkers correlated highly with one another including TNE-2 with NNAL and N-Acetyl-S-(2-cyanoethyl)-L-cysteine (2CYEMA), and N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (t4HBEMA) with N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (3HMPMA) and N-Acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (4HMBEMA). Lung cancer risk increased with concentration for several biomarkers, including TNE-2 (OR = 2.22, 95% CI = 1.03, 4.78) and NNN (OR = 2.44, 95% CI = 1.13, 5.27), and estimates were significant after further adjustment for demographic and smoking characteristics for 2CYEMA (OR = 2.17, 95% CI = 1.03, 4.55), N-Acetyl-S-(2-carbamoylethyl)-L-cysteine (2CAEMA) (OR = 2.14, 95% CI = 1.01, 4.55), and N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA) (OR = 2.85, 95% CI = 1.04, 7.81). Estimates were not significant with adjustment for opium use. Concentrations of many biomarkers were higher at the baseline for participants who subsequently developed lung cancer than among the matched controls. Odds of lung cancer were higher for several biomarkers including with adjustment for smoking exposure for some but not with adjustment for opium use. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
Concentrations of cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in US non-daily cigarette smokers
Gutiérrez-Torres DS , Wang L , Blount BC , Xia B , Sosnoff CS , Shiels MS , Inoue-Choi M , Etemadi A , Freedman ND . Cancer Epidemiol Biomarkers Prev 2021 30 (6) 1165-1174 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 2007-2014 National Health and Nutrition Examination Surveys, in comparison with daily smokers and non-smokers. 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 (non-smokers), 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 non-smokers had cotinine concentrations in the active smoking range (>10 ng/mL), compared to 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 non-smokers (Median: 0.4, IQR: 0.4-2.1 pg/mL), though 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 (P<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. |
Serum concentrations of per- and polyfluoroalkyl substances and risk of renal cell carcinoma
Shearer JJ , Callahan CL , Calafat AM , Huang WY , Jones RR , Sabbisetti VS , Freedman ND , Sampson JN , Silverman DT , Purdue MP , Hofmann JN . J Natl Cancer Inst 2020 113 (5) 580-587 BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of > 98% of the U.S. 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 pre-diagnostic serum concentrations of PFOA and seven 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 two-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 two-fold 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 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. |
Opiate and tobacco use and exposure to carcinogens and toxicants in Golestan Cohort Study
Etemadi A , Poustchi H , Calafat AM , Blount BC , De Jesus VR , Wang L , Pourshams A , Shakeri R , Inoue-Choi M , Shiels MS , Roshandel G , Murphy G , Sosnoff CS , Bhandari D , Feng J , Xia B , Wang Y , Meng L , Kamangar F , Brennan P , Boffetta P , Dawsey SM , Abnet CC , Malekzadeh R , Freedman ND . Cancer Epidemiol Biomarkers Prev 2020 29 (3) 650-658 BACKGROUND: There is little information on human exposure to carcinogens and toxicants related to opiate use, alone or combined with tobacco. METHODS: Among male participants of the Golestan Cohort Study in Northeast Iran, we studied 28 never users of either opiates or tobacco, 33 exclusive cigarette smokers, 23 exclusive users of smoked opiates, and 30 opiate users who also smoked cigarettes (dual users; 21 smoked opiates and 9 ingested them). We quantified urinary concentrations of 39 exposure biomarkers: tobacco alkaloids, tobacco specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs) and used decomposition to parse out the share of the biomarker concentrations explained by opiate use and nicotine dose. RESULTS: Dual users had the highest concentrations of all biomarkers, but exclusive cigarette smokers and exclusive opiate users had substantially higher concentrations of PAH and VOC biomarkers than never users. Decomposition analysis showed that opiate use contributed a larger part of the PAH concentrations than nicotine dose, and the sum of 2- and 3-hydroxyphenanthrene ( summation operator2,3-phe) resulted almost completely from opiate use. Two acrylamide metabolites, a 1,3-butadiene metabolite, and a dimethylformamide metabolite were more strongly explained by opiate use. Acrylamide metabolites and summation operator2,3-phe were significantly higher in opiate smokers than opiate eaters; other biomarkers did not vary by the route of opiate intake. CONCLUSION: Both cigarette smokers and opiate users (by smoking or ingestion) were exposed to many toxicants and carcinogens. IMPACT: This high exposure, particularly among dual opiates and cigarette users can have substantial global public health impact. |
Urinary biomarkers of carcinogenic exposure among cigarette, waterpipe and smokeless tobacco users and never users of tobacco in the Golestan Cohort Study
Etemadi A , Poustchi H , Chang CM , Blount BC , Calafat AM , Wang L , De Jesus VR , Pourshams A , Shakeri R , Shiels MS , Inoue-Choi M , Ambrose BK , Christensen CH , Wang B , Murphy G , Ye X , Bhandari D , Feng J , Xia B , Sosnoff CS , Kamangar F , Brennan P , Boffetta P , Dawsey SM , Abnet CC , Malekzadeh R , Freedman ND . Cancer Epidemiol Biomarkers Prev 2019 28 (2) 337-347 BACKGROUND: How carcinogen exposure varies across users of different, particularly non-cigarette, tobacco products remains poorly understood. METHODS: We randomly selected 165 participants of Golestan Cohort Study from northeastern Iran: 60 never users of any tobacco, 35 exclusive cigarette, 40 exclusive (78% daily) waterpipe, and 30 exclusive smokeless tobacco (nass) users. We measured concentrations of 39 biomarkers of exposure in 4 chemical classes in baseline urine samples: tobacco alkaloids, tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs). We also quantified the same biomarkers in a second urine sample, obtained five years later, among continuing cigarette smokers and never tobacco users. RESULTS: Nass users had the highest concentrations of tobacco alkaloids. All tobacco users had elevated TSNA concentrations which correlated with nicotine dose. In both cigarette and waterpipe smokers, PAH and VOC biomarkers were higher than never tobacco users and nass users, and highly correlated with nicotine dose. PAH biomarkers of phenanthrene and pyrene, and two VOC metabolites (phenylmercapturic acid and phenylglyoxylic acid) were higher in waterpipe smokers than all other groups. PAH biomarkers among Golestan never tobacco users were comparable to those in U.S. cigarette smokers. All biomarkers had moderate to good correlations over five years, particularly in continuing cigarette smokers. CONCLUSION: We observed two patterns of exposure biomarkers that differentiated the use of the combustible products (cigarettes and waterpipe) from the smokeless product. Environmental exposure from non-tobacco sources appeared to contribute to the presence of high levels of PAH metabolites in the Golestan Cohort. |
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome.
Machiela MJ , Zhou W , Karlins E , Sampson JN , Freedman ND , Yang Q , Hicks B , Dagnall C , Hautman C , Jacobs KB , Abnet CC , Aldrich MC , Amos C , Amundadottir LT , Arslan AA , Beane-Freeman LE , Berndt SI , Black A , Blot WJ , Bock CH , Bracci PM , Brinton LA , Bueno-de-Mesquita HB , Burdett L , Buring JE , Butler MA , Canzian F , Carreon T , Chaffee KG , Chang IS , Chatterjee N , Chen C , Chen C , Chen K , Chung CC , Cook LS , Crous Bou M , Cullen M , Davis FG , De Vivo I , Ding T , Doherty J , Duell EJ , Epstein CG , Fan JH , Figueroa JD , Fraumeni JF , Friedenreich CM , Fuchs CS , Gallinger S , Gao YT , Gapstur SM , Garcia-Closas M , Gaudet MM , Gaziano JM , Giles GG , Gillanders EM , Giovannucci EL , Goldin L , Goldstein AM , Haiman CA , Hallmans G , Hankinson SE , Harris CC , Henriksson R , Holly EA , Hong YC , Hoover RN , Hsiung CA , Hu N , Hu W , Hunter DJ , Hutchinson A , Jenab M , Johansen C , Khaw KT , Kim HN , Kim YH , Kim YT , Klein AP , Klein R , Koh WP , Kolonel LN , Kooperberg C , Kraft P , Krogh V , Kurtz RC , LaCroix A , Lan Q , Landi MT , Marchand LL , Li D , Liang X , Liao LM , Lin D , Liu J , Lissowska J , Lu L , Magliocco AM , Malats N , Matsuo K , McNeill LH , McWilliams RR , Melin BS , Mirabello L , Moore L , Olson SH , Orlow I , Park JY , Patino-Garcia A , Peplonska B , Peters U , Petersen GM , Pooler L , Prescott J , Prokunina-Olsson L , Purdue MP , Qiao YL , Rajaraman P , Real FX , Riboli E , Risch HA , Rodriguez-Santiago B , Ruder AM , Savage SA , Schumacher F , Schwartz AG , Schwartz KL , Seow A , Wendy Setiawan V , Severi G , Shen H , Sheng X , Shin MH , Shu XO , Silverman DT , Spitz MR , Stevens VL , Stolzenberg-Solomon R , Stram D , Tang ZZ , Taylor PR , Teras LR , Tobias GS , Van Den Berg D , Visvanathan K , Wacholder S , Wang JC , Wang Z , Wentzensen N , Wheeler W , White E , Wiencke JK , Wolpin BM , Wong MP , Wu C , Wu T , Wu X , Wu YL , Wunder JS , Xia L , Yang HP , Yang PC , Yu K , Zanetti KA , Zeleniuch-Jacquotte A , Zheng W , Zhou B , Ziegler RG , Perez-Jurado LA , Caporaso NE , Rothman N , Tucker M , Dean MC , Yeager M , Chanock SJ . Nat Commun 2016 7 11843 To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases. |
Characterization of large structural genetic mosaicism in human autosomes.
Machiela MJ , Zhou W , Sampson JN , Dean MC , Jacobs KB , Black A , Brinton LA , Chang IS , Chen C , Chen C , Chen K , Cook LS , Crous Bou M , De Vivo I , Doherty J , Friedenreich CM , Gaudet MM , Haiman CA , Hankinson SE , Hartge P , Henderson BE , Hong YC , Hosgood HD 3rd , Hsiung CA , Hu W , Hunter DJ , Jessop L , Kim HN , Kim YH , Kim YT , Klein R , Kraft P , Lan Q , Lin D , Liu J , Le Marchand L , Liang X , Lissowska J , Lu L , Magliocco AM , Matsuo K , Olson SH , Orlow I , Park JY , Pooler L , Prescott J , Rastogi R , Risch HA , Schumacher F , Seow A , Setiawan VW , Shen H , Sheng X , Shin MH , Shu XO , VanDen Berg D , Wang JC , Wentzensen N , Wong MP , Wu C , Wu T , Wu YL , Xia L , Yang HP , Yang PC , Zheng W , Zhou B , Abnet CC , Albanes D , Aldrich MC , Amos C , Amundadottir LT , Berndt SI , Blot WJ , Bock CH , Bracci PM , Burdett L , Buring JE , Butler MA , Carreon T , Chatterjee N , Chung CC , Cook MB , Cullen M , Davis FG , Ding T , Duell EJ , Epstein CG , Fan JH , Figueroa JD , Fraumeni JF Jr , Freedman ND , Fuchs CS , Gao YT , Gapstur SM , Patino-Garcia A , Garcia-Closas M , Gaziano JM , Giles GG , Gillanders EM , Giovannucci EL , Goldin L , Goldstein AM , Greene MH , Hallmans G , Harris CC , Henriksson R , Holly EA , Hoover RN , Hu N , Hutchinson A , Jenab M , Johansen C , Khaw KT , Koh WP , Kolonel LN , Kooperberg C , Krogh V , Kurtz RC , LaCroix A , Landgren A , Landi MT , Li D , Liao LM , Malats N , McGlynn KA , McNeill LH , McWilliams RR , Melin BS , Mirabello L , Peplonska B , Peters U , Petersen GM , Prokunina-Olsson L , Purdue M , Qiao YL , Rabe KG , Rajaraman P , Real FX , Riboli E , Rodriguez-Santiago B , Rothman N , Ruder AM , Savage SA , Schwartz AG , Schwartz KL , Sesso HD , Severi G , Silverman DT , Spitz MR , Stevens VL , Stolzenberg-Solomon R , Stram D , Tang ZZ , Taylor PR , Teras LR , Tobias GS , Viswanathan K , Wacholder S , Wang Z , Weinstein SJ , Wheeler W , White E , Wiencke JK , Wolpin BM , Wu X , Wunder JS , Yu K , Zanetti KA , Zeleniuch-Jacquotte A , Ziegler RG , de Andrade M , Barnes KC , Beaty TH , Bierut LJ , Desch KC , Doheny KF , Feenstra B , Ginsburg D , Heit JA , Kang JH , Laurie CA , Li JZ , Lowe WL , Marazita ML , Melbye M , Mirel DB , Murray JC , Nelson SC , Pasquale LR , Rice K , Wiggs JL , Wise A , Tucker M , Perez-Jurado LA , Laurie CC , Caporaso NE , Yeager M , Chanock SJ . Am J Hum Genet 2015 96 (3) 487-97 Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. |
Beta-diversity metrics of the upper digestive tract microbiome are associated with body mass index.
Lin SW , Freedman ND , Shi J , Gail MH , Vogtmann E , Yu G , Klepac-Ceraj V , Paster BJ , Dye BA , Wang GQ , Wei WQ , Fan JH , Qiao YL , Dawsey SM , Abnet CC . Obesity (Silver Spring) 2015 23 (4) 862-9 OBJECTIVE: Studies of the fecal microbiome have implicated the gut microbiota in obesity, but few studies have examined the microbial diversity at other sites. The association between obesity and the upper gastrointestinal (UGI) microbial diversity was explored. METHODS: The UGI microbiome of 659 healthy Chinese adults with a measured body mass index (BMI) range of 15.0 to 35.7 was characterized using the 16S rRNA gene DNA microarray (HOMIM). RESULTS: In multivariate-adjusted models, alpha diversity was not associated with BMI. However, beta diversity, assessed by principal coordinate vectors generated from an unweighted UniFrac distance matrix of pairwise comparisons, was associated with BMI (third and fourth vectors, P = 0.01 and P = 0.03, respectively). Moreover, beta diversity, assessed by cluster membership (three clusters), was also associated with BMI; individuals in the first cluster [median BMI 22.35, odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.05-4.34] and second cluster [median BMI 22.55, OR = 0.26, 95% CI = 0.09-0.75] were significantly less likely to be obese (BMI ≥ 27.5) than those in the third cluster (median BMI 23.59). CONCLUSIONS: A beta-diversity metric of the UGI microbiome is associated with a four fold difference in obesity risk in this Asian population. Future studies should address whether the UGI microbiome plays a causal role in obesity. |
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Wang Z , Zhu B , Zhang M , Parikh H , Jia J , Chung CC , Sampson JN , Hoskins JW , Hutchinson A , Burdette L , Ibrahim A , Hautman C , Raj PS , Abnet CC , Adjei AA , Ahlbom A , Albanes D , Allen NE , Ambrosone CB , Aldrich M , Amiano P , Amos C , Andersson U , Andriole G Jr , Andrulis IL , Arici C , Arslan AA , Austin MA , Baris D , Barkauskas DA , Bassig BA , Beane Freeman LE , Berg CD , Berndt SI , Bertazzi PA , Biritwum RB , Black A , Blot W , Boeing H , Boffetta P , Bolton K , Boutron-Ruault MC , Bracci PM , Brennan P , Brinton LA , Brotzman M , Bueno-de-Mesquita HB , Buring JE , Butler MA , Cai Q , Cancel-Tassin G , Canzian F , Cao G , Caporaso NE , Carrato A , Carreon T , Carta A , Chang GC , Chang IS , Chang-Claude J , Che X , Chen CJ , Chen CY , Chen CH , Chen C , Chen KY , Chen YM , Chokkalingam AP , Chu LW , Clavel-Chapelon F , Colditz GA , Colt JS , Conti D , Cook MB , Cortessis VK , Crawford ED , Cussenot O , Davis FG , De Vivo I , Deng X , Ding T , Dinney CP , Di Stefano AL , Diver WR , Duell EJ , Elena JW , Fan JH , Feigelson HS , Feychting M , Figueroa JD , Flanagan AM , Fraumeni JF Jr , Freedman ND , Fridley BL , Fuchs CS , Gago-Dominguez M , Gallinger S , Gao YT , Gapstur SM , Garcia-Closas M , Garcia-Closas R , Gastier-Foster JM , Gaziano JM , Gerhard DS , Giffen CA , Giles GG , Gillanders EM , Giovannucci EL , Goggins M , Gokgoz N , Goldstein AM , Gonzalez C , Gorlick R , Greene MH , Gross M , Grossman HB , Grubb R 3rd , Gu J , Guan P , Haiman CA , Hallmans G , Hankinson SE , Harris CC , Hartge P , Hattinger C , Hayes RB , He Q , Helman L , Henderson BE , Henriksson R , Hoffman-Bolton J , Hohensee C , Holly EA , Hong YC , Hoover RN , Hosgood HD 3rd , Hsiao CF , Hsing AW , Hsiung CA , Hu N , Hu W , Hu Z , Huang MS , Hunter DJ , Inskip PD , Ito H , Jacobs EJ , Jacobs KB , Jenab M , Ji BT , Johansen C , Johansson M , Johnson A , Kaaks R , Kamat AM , Kamineni A , Karagas M , Khanna C , Khaw KT , Kim C , Kim IS , Kim YH , Kim YC , Kim YT , Kang CH , Jung YJ , Kitahara CM , Klein AP , Klein R , Kogevinas M , Koh WP , Kohno T , Kolonel LN , Kooperberg C , Kratz CP , Krogh V , Kunitoh H , Kurtz RC , Kurucu N , Lan Q , Lathrop M , Lau CC , Lecanda F , Lee KM , Lee MP , Le Marchand L , Lerner SP , Li D , Liao LM , Lim WY , Lin D , Lin J , Lindstrom S , Linet MS , Lissowska J , Liu J , Ljungberg B , Lloreta J , Lu D , Ma J , Malats N , Mannisto S , Marina N , Mastrangelo G , Matsuo K , McGlynn KA , McKean-Cowdin R , McNeill LH , McWilliams RR , Melin BS , Meltzer PS , Mensah JE , Miao X , Michaud DS , Mondul AM , Moore LE , Muir K , Niwa S , Olson SH , Orr N , Panico S , Park JY , Patel AV , Patino-Garcia A , Pavanello S , Peeters PH , Peplonska B , Peters U , Petersen GM , Picci P , Pike MC , Porru S , Prescott J , Pu X , Purdue MP , Qiao YL , Rajaraman P , Riboli E , Risch HA , Rodabough RJ , Rothman N , Ruder AM , Ryu JS , Sanson M , Schned A , Schumacher FR , Schwartz AG , Schwartz KL , Schwenn M , Scotlandi K , Seow A , Serra C , Serra M , Sesso HD , Severi G , Shen H , Shen M , Shete S , Shiraishi K , Shu XO , Siddiq A , Sierrasesumaga L , Sierri S , Sihoe AD , Silverman DT , Simon M , Southey MC , Spector L , Spitz M , Stampfer M , Stattin P , Stern MC , Stevens VL , Stolzenberg-Solomon RZ , Stram DO , Strom SS , Su WC , Sund M , Sung SW , Swerdlow A , Tan W , Tanaka H , Tang W , Tang ZZ , Tardon A , Tay E , Taylor PR , Tettey Y , Thomas DM , Tirabosco R , Tjonneland A , Tobias GS , Toro JR , Travis RC , Trichopoulos D , Troisi R , Truelove A , Tsai YH , Tucker MA , Tumino R , Van Den Berg D , Van Den Eeden SK , Vermeulen R , Vineis P , Visvanathan K , Vogel U , Wang C , Wang C , Wang J , Wang SS , Weiderpass E , Weinstein SJ , Wentzensen N , Wheeler W , White E , Wiencke JK , Wolk A , Wolpin BM , Wong MP , Wrensch M , Wu C , Wu T , Wu X , Wu YL , Wunder JS , Xiang YB , Xu J , Yang HP , Yang PC , Yatabe Y , Ye Y , Yeboah ED , Yin Z , Ying C , Yu CJ , Yu K , Yuan JM , Zanetti KA , Zeleniuch-Jacquotte A , Zheng W , Zhou B , Mirabello L , Savage SA , Kraft P , Chanock SJ , Yeager M , Landi MT , Shi J , Chatterjee N , Amundadottir LT . Hum Mol Genet 2014 23 (24) 6616-33 Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. |
Association between upper digestive tract microbiota and cancer-predisposing states in the esophagus and stomach
Yu G , Gail MH , Shi J , Klepac-Ceraj V , Paster BJ , Dye BA , Wang GQ , Wei WQ , Fan JH , Qiao YL , Dawsey SM , Freedman ND , Abnet CC . Cancer Epidemiol Biomarkers Prev 2014 23 (5) 735-41 BACKGROUND: The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer-predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II; predictor of gastric cancer risk) and esophageal squamous dysplasia (ESD; the precursor lesion of esophageal squamous cell carcinoma; ESCC) in a cross-sectional design. METHODS: The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by ELISA. ESD was determined by chromoendoscopy with biopsy. RESULTS: Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio (P = 0.034) and the presence of ESD (P = 0.018). We conducted principal component (PC) analysis on a beta-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3, and PGI/II (P = 0.004 and 0.009, respectively), and between PC1 and ESD (P = 0.003). CONCLUSIONS: Lower microbial richness in upper digestive tract was independently associated with both cancer-predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II). IMPACT: These novel findings suggest that the upper digestive tract microbiota may play a role in the etiology of chronic atrophic gastritis and ESD, and therefore in the development of gastric and esophageal cancers. |
Detectable clonal mosaicism and its relationship to aging and cancer.
Jacobs KB , Yeager M , Zhou W , Wacholder S , Wang Z , Rodriguez-Santiago B , Hutchinson A , Deng X , Liu C , Horner MJ , Cullen M , Epstein CG , Burdett L , Dean MC , Chatterjee N , Sampson J , Chung CC , Kovaks J , Gapstur SM , Stevens VL , Teras LT , Gaudet MM , Albanes D , Weinstein SJ , Virtamo J , Taylor PR , Freedman ND , Abnet CC , Goldstein AM , Hu N , Yu K , Yuan JM , Liao L , Ding T , Qiao YL , Gao YT , Koh WP , Xiang YB , Tang ZZ , Fan JH , Aldrich MC , Amos C , Blot WJ , Bock CH , Gillanders EM , Harris CC , Haiman CA , Henderson BE , Kolonel LN , Le Marchand L , McNeill LH , Rybicki BA , Schwartz AG , Signorello LB , Spitz MR , Wiencke JK , Wrensch M , Wu X , Zanetti KA , Ziegler RG , Figueroa JD , Garcia-Closas M , Malats N , Marenne G , Prokunina-Olsson L , Baris D , Schwenn M , Johnson A , Landi MT , Goldin L , Consonni D , Bertazzi PA , Rotunno M , Rajaraman P , Andersson U , Freeman LE , Berg CD , Buring JE , Butler MA , Carreon T , Feychting M , Ahlbom A , Gaziano JM , Giles GG , Hallmans G , Hankinson SE , Hartge P , Henriksson R , Inskip PD , Johansen C , Landgren A , McKean-Cowdin R , Michaud DS , Melin BS , Peters U , Ruder AM , Sesso HD , Severi G , Shu XO , Visvanathan K , White E , Wolk A , Zeleniuch-Jacquotte A , Zheng W , Silverman DT , Kogevinas M , Gonzalez JR , Villa O , Li D , Duell EJ , Risch HA , Olson SH , Kooperberg C , Wolpin BM , Jiao L , Hassan M , Wheeler W , Arslan AA , Bueno-de-Mesquita HB , Fuchs CS , Gallinger S , Gross MD , Holly EA , Klein AP , LaCroix A , Mandelson MT , Petersen G , Boutron-Ruault MC , Bracci PM , Canzian F , Chang K , Cotterchio M , Giovannucci EL , Goggins M , Hoffman Bolton JA , Jenab M , Khaw KT , Krogh V , Kurtz RC , McWilliams RR , Mendelsohn JB , Rabe KG , Riboli E , Tjønneland A , Tobias GS , Trichopoulos D , Elena JW , Yu H , Amundadottir L , Stolzenberg-Solomon RZ , Kraft P , Schumacher F , Stram D , Savage SA , Mirabello L , Andrulis IL , Wunder JS , Patiño García A , Sierrasesúmaga L , Barkauskas DA , Gorlick RG , Purdue M , Chow WH , Moore LE , Schwartz KL , Davis FG , Hsing AW , Berndt SI , Black A , Wentzensen N , Brinton LA , Lissowska J , Peplonska B , McGlynn KA , Cook MB , Graubard BI , Kratz CP , Greene MH , Erickson RL , Hunter DJ , Thomas G , Hoover RN , Real FX , Fraumeni JF Jr , Caporaso NE , Tucker M , Rothman N , Pérez-Jurado LA , Chanock SJ . Nat Genet 2012 44 (6) 651-8 In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases. |
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