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1.  Cancer Risk Following Pernicious Anemia in the US Elderly Population 
Background & Aims
Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2%–5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies indicated that patients with pernicious anemia could have an increased risk of cancer.
We performed a population-based, case–control study of individuals the SEER-Medicare database, comparing 1,138,390 cancer cases (66–99 y old) to 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection.
Compared with controls, we found individuals with pernicious anemia to be at increased risk for non-cardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94–2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90–14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40–2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35–2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76–2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32–2.02), liver cancer (OR, 1.49; 95% CI, 1.28– 1.73), myeloma (OR, 1.55; 95% CI, 1.37–1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46–1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53–3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74– 0.92).
In a population-based, case–control study of individuals the SEER-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.
PMCID: PMC4655146  PMID: 26079040
chronic atrophic autoimmune gastritis; acid secretion; parietal cells; stomach cancer
2.  Multiplex H. pylori serology and risk of gastric cardia and non-cardia adenocarcinomas 
Cancer research  2015;75(22):4876-4883.
The reported associations with gastric adenocarcinoma and seropositivity to different H. pylori antigens using multiplex serology have not been consistent across studies. We aimed to investigate the association between fifteen different multiplex serology antigens and the risk of gastric cardia (GCA) and gastric non-cardia (GNCA) adenocarcinomas in northeastern Iran, a population with high rates of gastric adenocarcinoma. We included 272 cases of gastric adenocarcinoma (142 GCA, 103 GNCA, and 27 unspecified) and 524 controls who were individually matched to cases for age, sex, and place of residence in a population-based case-control study. Seropositivity to H. pylori was assessed using both multiplex serology and H. pylori IgG ELISA. 95% of controls were seropositive to H. pylori. Of the 15 antibodies in the multiplex assay, 11 showed no significant association with gastric adenocarcinomas. CagA and VacA were associated with a significantly increased risk of all gastric adenocarcinoma and GNCA in multivariate models. Surprisingly, GroEL and NapA were significantly associated with a reduced risk of these tumors. Only CagA antigen was associated with significantly elevated risk of GCA. We found no associations between H. pylori seropositivity overall either by whole-cell ELISA test or multiplex serology, likely due to the high prevalence of seropositivity. Individual antigen testing showed that CagA positivity was associated with increased risk of both noncardia and cardia adenocarcinoma, which is similar to some other Asian populations, while two antigens were associated with lower risk of gastric cancer. This latter result was unexpected and should be re-tested in other populations.
PMCID: PMC4792189  PMID: 26383162
3.  Heart disease is associated with anthropometric indices and change in body size perception over the life course: The Golestan Cohort Study 
Global heart  2015;10(4):245-254.e1.
Cardiovascular disease and obesity are now becoming leading causes of morbidity and mortality in low- and middle-income countries (LMICs). We investigated the relationship between prevalent heart disease (HD) and current anthropometric indices and body size perception over time from adolescence to adulthood in Iran.
We present a cross-sectional analysis of baseline data from a prospective study of adults in Golestan Province, Iran. Demographics, cardiac history, and current anthropometric indices—body mass index (BMI), waist circumference (WC), and waist to hip ratio (WHR)—were recorded. Body size perception for age 15, age 30, and at the time of interview was assessed via pictograms. Associations of these factors and temporal change in perceived body size with HD were evaluated using multivariable logistic regression models.
Complete data were available for 50,044 participants; 6.1% reported having HD. Higher BMI, WC, and WHR were associated with HD (p < 0.001). Men had a U-shaped relationship between HD and body size perception at younger ages. For change in body size perception, men and women demonstrated a U-shaped relationship with prevalent HD from adolescence to early adulthood, but a J-shaped pattern from early to late adulthood.
HD was associated with anthropometric indices and change in body size perception over time for men and women in Iran. Due to the increasing prevalence of overweight and obesity in LMICs, interventions focused on decreasing the cumulative burden of risk factors throughout the life course may be an important component of cardiovascular risk reduction.
PMCID: PMC4561595  PMID: 26014653
body size perception; body mass index; heart disease; prevalence; middle-income country
4.  Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types 
Sampson, Joshua N. | Wheeler, William A. | Yeager, Meredith | Panagiotou, Orestis | Wang, Zhaoming | Berndt, Sonja I. | Lan, Qing | Abnet, Christian C. | Amundadottir, Laufey T. | Figueroa, Jonine D. | Landi, Maria Teresa | Mirabello, Lisa | Savage, Sharon A. | Taylor, Philip R. | Vivo, Immaculata De | McGlynn, Katherine A. | Purdue, Mark P. | Rajaraman, Preetha | Adami, Hans-Olov | Ahlbom, Anders | Albanes, Demetrius | Amary, Maria Fernanda | An, She-Juan | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Angelucci, Emanuele | Ansell, Stephen M. | Arici, Cecilia | Armstrong, Bruce K. | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Becker, Nikolaus | Benavente, Yolanda | Benhamou, Simone | Berg, Christine | Van Den Berg, David | Bernstein, Leslie | Bertrand, Kimberly A. | Birmann, Brenda M. | Black, Amanda | Boeing, Heiner | Boffetta, Paolo | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brinton, Louise | Brooks-Wilson, Angela R. | Bueno-de-Mesquita, H. Bas | Burdett, Laurie | Buring, Julie | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chan, John K. C. | Chang, Ellen T. | Chang, Gee-Chen | Chang, I-Shou | Chang, Jiang | Chang-Claude, Jenny | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chu | Chen, Chung-Hsing | Chen, Constance | Chen, Hongyan | Chen, Kexin | Chen, Kuan-Yu | Chen, Kun-Chieh | Chen, Ying | Chen, Ying-Hsiang | Chen, Yi-Song | Chen, Yuh-Min | Chien, Li-Hsin | Chirlaque, María-Dolores | Choi, Jin Eun | Choi, Yi Young | Chow, Wong-Ho | Chung, Charles C. | Clavel, Jacqueline | Clavel-Chapelon, Françoise | Cocco, Pierluigi | Colt, Joanne S. | Comperat, Eva | Conde, Lucia | Connors, Joseph M. | Conti, David | Cortessis, Victoria K. | Cotterchio, Michelle | Cozen, Wendy | Crouch, Simon | Crous-Bou, Marta | Cussenot, Olivier | Davis, Faith G. | Ding, Ti | Diver, W. Ryan | Dorronsoro, Miren | Dossus, Laure | Duell, Eric J. | Ennas, Maria Grazia | Erickson, Ralph L. | Feychting, Maria | Flanagan, Adrienne M. | Foretova, Lenka | Fraumeni, Joseph F. | Freedman, Neal D. | Beane Freeman, Laura E. | Fuchs, Charles | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | García-Closas, Reina | Gascoyne, Randy D. | Gastier-Foster, Julie | Gaudet, Mia M. | Gaziano, J. Michael | Giffen, Carol | Giles, Graham G. | Giovannucci, Edward | Glimelius, Bengt | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gorlick, Richard | Gross, Myron | Grubb, Robert | Gu, Jian | Guan, Peng | Gunter, Marc | Guo, Huan | Habermann, Thomas M. | Haiman, Christopher A. | Halai, Dina | Hallmans, Goran | Hassan, Manal | Hattinger, Claudia | He, Qincheng | He, Xingzhou | Helzlsouer, Kathy | Henderson, Brian | Henriksson, Roger | Hjalgrim, Henrik | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holford, Theodore R. | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Horn-Ross, Pamela L. | Hosain, G. M. Monawar | Hosgood, H. Dean | Hsiao, Chin-Fu | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Huerta, Jose-Maria | Hung, Jen-Yu | Hutchinson, Amy | Inskip, Peter D. | Jackson, Rebecca D. | Jacobs, Eric J. | Jenab, Mazda | Jeon, Hyo-Sung | Ji, Bu-Tian | Jin, Guangfu | Jin, Li | Johansen, Christoffer | Johnson, Alison | Jung, Yoo Jin | Kaaks, Rudolph | Kamineni, Aruna | Kane, Eleanor | Kang, Chang Hyun | Karagas, Margaret R. | Kelly, Rachel S. | Khaw, Kay-Tee | Kim, Christopher | Kim, Hee Nam | Kim, Jin Hee | Kim, Jun Suk | Kim, Yeul Hong | Kim, Young Tae | Kim, Young-Chul | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert J. | Kogevinas, Manolis | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kricker, Anne | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kweon, Sun-Seog | LaCroix, Andrea | Lawrence, Charles | Lecanda, Fernando | Lee, Victor Ho Fun | Li, Donghui | Li, Haixin | Li, Jihua | Li, Yao-Jen | Li, Yuqing | Liao, Linda M. | Liebow, Mark | Lightfoot, Tracy | Lim, Wei-Yen | Lin, Chien-Chung | Lin, Dongxin | Lindstrom, Sara | Linet, Martha S. | Link, Brian K. | Liu, Chenwei | Liu, Jianjun | Liu, Li | Ljungberg, Börje | Lloreta, Josep | Lollo, Simonetta Di | Lu, Daru | Lund, Eiluv | Malats, Nuria | Mannisto, Satu | Marchand, Loic Le | Marina, Neyssa | Masala, Giovanna | Mastrangelo, Giuseppe | Matsuo, Keitaro | Maynadie, Marc | McKay, James | McKean-Cowdin, Roberta | Melbye, Mads | Melin, Beatrice S. | Michaud, Dominique S. | Mitsudomi, Tetsuya | Monnereau, Alain | Montalvan, Rebecca | Moore, Lee E. | Mortensen, Lotte Maxild | Nieters, Alexandra | North, Kari E. | Novak, Anne J. | Oberg, Ann L. | Offit, Kenneth | Oh, In-Jae | Olson, Sara H. | Palli, Domenico | Pao, William | Park, In Kyu | Park, Jae Yong | Park, Kyong Hwa | Patiño-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Perng, Reury-Perng | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Qian, Biyun | Qiao, You-Lin | Rais, Marco | Riboli, Elio | Riby, Jacques | Risch, Harvey A. | Rizzato, Cosmeri | Rodabough, Rebecca | Roman, Eve | Roupret, Morgan | Ruder, Avima M. | de Sanjose, Silvia | Scelo, Ghislaine | Schned, Alan | Schumacher, Fredrick | Schwartz, Kendra | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Setiawan, Veronica Wendy | Severi, Gianluca | Severson, Richard K. | Shanafelt, Tait D. | Shen, Hongbing | Shen, Wei | Shin, Min-Ho | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesúmaga, Luis | Sihoe, Alan Dart Loon | Skibola, Christine F. | Smith, Alex | Smith, Martyn T. | Southey, Melissa C. | Spinelli, John J. | Staines, Anthony | Stampfer, Meir | Stern, Marianna C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael S. | Su, Jian | Su, Wu-Chou | Sund, Malin | Sung, Jae Sook | Sung, Sook Whan | Tan, Wen | Tang, Wei | Tardón, Adonina | Thomas, David | Thompson, Carrie A. | Tinker, Lesley F. | Tirabosco, Roberto | Tjønneland, Anne | Travis, Ruth C. | Trichopoulos, Dimitrios | Tsai, Fang-Yu | Tsai, Ying-Huang | Tucker, Margaret | Turner, Jenny | Vajdic, Claire M. | Vermeulen, Roel C. H. | Villano, Danylo J. | Vineis, Paolo | Virtamo, Jarmo | Visvanathan, Kala | Wactawski-Wende, Jean | Wang, Chaoyu | Wang, Chih-Liang | Wang, Jiu-Cun | Wang, Junwen | Wei, Fusheng | Weiderpass, Elisabete | Weiner, George J. | Weinstein, Stephanie | Wentzensen, Nicolas | White, Emily | Witzig, Thomas E. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Guoping | Wu, Junjie | Wu, Tangchun | Wu, Wei | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Xu, Ping | Yang, Pan-Chyr | Yang, Tsung-Ying | Ye, Yuanqing | Yin, Zhihua | Yokota, Jun | Yoon, Ho-Il | Yu, Chong-Jen | Yu, Herbert | Yu, Kai | Yuan, Jian-Min | Zelenetz, Andrew | Zeleniuch-Jacquotte, Anne | Zhang, Xu-Chao | Zhang, Yawei | Zhao, Xueying | Zhao, Zhenhong | Zheng, Hong | Zheng, Tongzhang | Zheng, Wei | Zhou, Baosen | Zhu, Meng | Zucca, Mariagrazia | Boca, Simina M. | Cerhan, James R. | Ferri, Giovanni M. | Hartge, Patricia | Hsiung, Chao Agnes | Magnani, Corrado | Miligi, Lucia | Morton, Lindsay M. | Smedby, Karin E. | Teras, Lauren R. | Vijai, Joseph | Wang, Sophia S. | Brennan, Paul | Caporaso, Neil E. | Hunter, David J. | Kraft, Peter | Rothman, Nathaniel | Silverman, Debra T. | Slager, Susan L. | Chanock, Stephen J. | Chatterjee, Nilanjan
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.
GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID: PMC4806328  PMID: 26464424
5.  Prospective study of serum B vitamins levels and oesophageal and gastric cancers in China 
Scientific Reports  2016;6:35281.
B vitamins play an essential role in DNA synthesis and methylation, and may protect against oesophageal and gastric cancers. In this case-cohort study, subjects were enrolled from the General Population Nutrition Intervention Trial in Linxian, China. Subjects included 498 oesophageal squamous cell carcinomas (OSCCs), 255 gastric cardia adenocarcinomas (GCAs), and an age- and sex-matched sub-cohort of 947 individuals. Baseline serum riboflavin, pyridoxal phosphate (PLP), folate, vitamin B12, and flavin mononucleotide (FMN) were measured for all subjects. We estimated the associations with Cox proportional hazard models, with adjustment for potential confounders. Compared to those in the lowest quartile of serum riboflavin, those in the highest had a 44% lower risk of OSCC (HR: 0.56, 95% CI: 0.41 to 0.75). Serum vitamin B12 as a continuous variable was observed to be significantly inversely associated with OSCC (HR: 0.95, 95% CI: 0.89 to 1.01, P for score test = 0.041). Higher serum FMN levels were significantly associated with increased risk of OSCC (HR: 1.08, 95% CI: 1.01 to 1.16) and GCA (HR: 1.09, 95% CI: 1.00 to 1.20). Our study prompted that B vitamins have the potential role as chemopreventive agents for upper gastrointestinal cancers.
PMCID: PMC5066215  PMID: 27748414
6.  Prospective study of Helicobacter pylori antigens and gastric noncardia cancer risk in the Nutrition Intervention Trial cohort 
Helicobacter pylon (H. pylori) infection is the strongest known risk factor for gastric non-cardia adenocarcinoma (GNCA). We used multiplex serology to determine whether seropositivity to 15 H. pylori proteins is associated with the subsequent development of non-cardia gastric cancer in Linxian, China.
We included 448 GNCA cases and 1242 controls from two time-points within the Linxian General Population Nutrition Intervention Trial, Linxian. H. pylori multiplex seropositivity was defined as positivity to ≥4 of the 15 included antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major GNCA risk factors. Additionally, we undertook a meta-analysis combining H. pylori multiplex serology data from both timepoints.
H. pylori multiplex seropositivity was associated with a significant increase in risk of GNCA at one time-point (1985; OR: 3.44, 95% CI: 1.91, 6.19) and this association remained significant following adjustment for H. pylori or CagA ELISA seropositivity (OR: 2.92, 95% CI: 1.56, 5.47). Combining data from both timepoints in a meta-analysis H. pylori multiplex seropositivity was associated with an increased risk of GNCA, as were 6 individual antigens: GroEL, HP0305, CagA, VacA, HcpC and Omp. CagM was inversely associated with risk of GNCA.
We identified 6 individual antigens which confer an increase in risk of GNCA within this population of high H. pylori seroprevalence, as well as a single antigen which may be inversely associated with GNCA risk. We further determined that the H. pylori multiplex assay provides additional information to the conventional ELISA methods on risk of GNCA.
PMCID: PMC4529753  PMID: 25845708
Helicobacter pylori; multiplex serology; gastric cancer; esophageal cancer
7.  Common genetic variants related to vitamin D status are not associated with esophageal squamous cell carcinoma risk in China 
Cancer epidemiology  2015;39(2):157-159.
Few studies have examined the association of common genetic variants related to vitamin D metabolism and signaling to esophageal squamous cell carcinoma(ESCC).
We evaluated the association between 12 single nucleotide polymorphisms(SNPs) in four genes related to vitamin D levels and ESCC risk using data from a genome-wide association study. Participants were recruited from the Shanxi Upper Gastrointestinal Cancer Genetics Project and the Linxian Nutrition Intervention Trials, and included 1942 ESCC cases and 2111controls. We used logistic models to estimate odds ratios(ORs) and 95% confidence intervals(CIs) for the SNP associations, after controlling for age and gender.
None of the 12 evaluated SNPs in the four vitamin D-related genes were significantly associated with risk of ESCC. The strongest associations were for rs3794060(P=0.07) and rs12800438(P=0.08) in the DHCR7/NADSYN1gene. No association between vitamin D-related SNPs and risk of ESCC was observed in a genotype score analysis that included all 12 SNPs. ORs for quartiles 2, 3 and 4 of the genotype scores were 0.83 (95% CI: 0.68, 1.01), 1.02(0.85, 1.21), and 1.08 (0.89, 1.30), respectively, with no evidence for a significant monotonic trend(P=0.120).
Our results suggested that common genetic variants related to vitamin D levels are not associated with risk of ESCC in this Chinese population.
PMCID: PMC4382354  PMID: 25631780
vitamin D; genetic variants; esophageal squamous cell carcinoma; China
8.  Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers 
Background: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk.
Methods: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses.
Results: Suggestive pathway-based associations were observed for the overall epigenetic (P-valuePATH = 0.034) and chromatin remodelling (P-valuePATH = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-valueGENE < 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues.
Conclusions: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.
PMCID: PMC4598798  PMID: 25921222
Epigenetics; chromatin remodelling; DNA methylation; microRNA; oesophageal squamous cell carcinoma; gastric cancer; gastric cardia; gastric non-cardia; SNP; gene-based; pathway-based
9.  The Nail as a Biomonitor of Trace Element Status in Golestan Cohort Study 
In the Golestan Cohort Study that was launched to investigate the causes of esophageal cancer, a complete biospecimen bank was established for storage of collected blood, urine, hair, and nail samples. The objective of this study was to evaluate the feasibility of nail samples as a biomarker of selected trace elements status.
Thirty toenail samples were selected randomly from the participants of Golestan Cohort Study (GCS). The samples were cleaned and analyzed for selenium, mercury, chromium, iron, zinc, and scandium by instrumental neutron activation analysis at the University of Missouri Research Reactor Center. Pearson correlation coefficients were computed for selected trace elements concentration versus scandium concentration to assess terrestrial contamination.
The selenium, zinc, and mercury were not correlated with scandium, suggesting they were free from substantial contamination. The high correlations of scandium with iron and chromium suggest that the iron and chromium levels may be compromised by terrestrial contamination. The coefficients of variation for duplicate samples for selenium and zinc were 2.6% and 7.2%, respectively.
The nail samples from Golestan Cohort Study appears to be useable as a biomarker of selenium, zinc, and mercury and could be considered for use in future studies.
PMCID: PMC4773078  PMID: 26933477
Minerals; Biomarker Validation; Toe nail; Selenium; Zinc; Golestan Cohort Study
10.  Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome 
Machiela, Mitchell J. | Zhou, Weiyin | Karlins, Eric | Sampson, Joshua N. | Freedman, Neal D. | Yang, Qi | Hicks, Belynda | Dagnall, Casey | Hautman, Christopher | Jacobs, Kevin B. | Abnet, Christian C. | Aldrich, Melinda C. | Amos, Christopher | Amundadottir, Laufey T. | Arslan, Alan A. | Beane-Freeman, Laura E. | Berndt, Sonja I. | Black, Amanda | Blot, William J. | Bock, Cathryn H. | Bracci, Paige M. | Brinton, Louise A. | Bueno-de-Mesquita, H Bas | Burdett, Laurie | Buring, Julie E. | Butler, Mary A. | Canzian, Federico | Carreón, Tania | Chaffee, Kari G. | Chang, I-Shou | Chatterjee, Nilanjan | Chen, Chu | Chen, Constance | Chen, Kexin | Chung, Charles C. | Cook, Linda S. | Crous Bou, Marta | Cullen, Michael | Davis, Faith G. | De Vivo, Immaculata | Ding, Ti | Doherty, Jennifer | Duell, Eric J. | Epstein, Caroline G. | Fan, Jin-Hu | Figueroa, Jonine D. | Fraumeni, Joseph F. | Friedenreich, Christine M. | Fuchs, Charles S. | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Gaudet, Mia M. | Gaziano, J. Michael | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goldin, Lynn | Goldstein, Alisa M. | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Henriksson, Roger | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hsiung, Chao A. | Hu, Nan | Hu, Wei | Hunter, David J. | Hutchinson, Amy | Jenab, Mazda | Johansen, Christoffer | Khaw, Kay-Tee | Kim, Hee Nam | Kim, Yeul Hong | Kim, Young Tae | Klein, Alison P. | Klein, Robert | Koh, Woon-Puay | Kolonel, Laurence N. | Kooperberg, Charles | Kraft, Peter | Krogh, Vittorio | Kurtz, Robert C. | LaCroix, Andrea | Lan, Qing | Landi, Maria Teresa | Marchand, Loic Le | Li, Donghui | Liang, Xiaolin | Liao, Linda M. | Lin, Dongxin | Liu, Jianjun | Lissowska, Jolanta | Lu, Lingeng | Magliocco, Anthony M. | Malats, Nuria | Matsuo, Keitaro | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Mirabello, Lisa | Moore, Lee | Olson, Sara H. | Orlow, Irene | Park, Jae Yong | Patiño-Garcia, Ana | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Pooler, Loreall | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Real, Francisco X. | Riboli, Elio | Risch, Harvey A. | Rodriguez-Santiago, Benjamin | Ruder, Avima M. | Savage, Sharon A. | Schumacher, Fredrick | Schwartz, Ann G. | Schwartz, Kendra L. | Seow, Adeline | Wendy Setiawan, Veronica | Severi, Gianluca | Shen, Hongbing | Sheng, Xin | Shin, Min-Ho | Shu, Xiao-Ou | Silverman, Debra T. | Spitz, Margaret R. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael | Stram, Daniel | Tang, Ze-Zhong | Taylor, Philip R. | Teras, Lauren R. | Tobias, Geoffrey S. | Van Den Berg, David | Visvanathan, Kala | Wacholder, Sholom | Wang, Jiu-Cun | Wang, Zhaoming | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xia, Lucy | Yang, Hannah P. | Yang, Pan-Chyr | Yu, Kai | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Ziegler, Regina G. | Perez-Jurado, Luis A. | Caporaso, Neil E. | Rothman, Nathaniel | Tucker, Margaret | Dean, Michael C. | Yeager, Meredith | Chanock, Stephen J.
Nature Communications  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.
It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk
PMCID: PMC4909985  PMID: 27291797
11.  Diet and Upper Gastrointestinal Malignancies 
Gastroenterology  2015;148(6):1234-1243.e4.
Diet is believed to modulate cancer risk and this relationship has been widely studied in the gastrointestinal tract. Observational epidemiologic studies have provided most of the evidence for the effects of diet on cancer risk, because clinical trials to determine nutritional exposures are often impossible, impractical, or unaffordable. Although a few foods or nutrients are thought to protect against specific types of cancer, it seems clear that the strength and even direction of dietary associations (increasing or decreasing risk) is organ site- and even histology-specific, along the gastrointestinal tract. Although some hypotheses are supported by a substantial body of observational data (drinking hot maté contributes to esophageal cancer), there is not much data to support others. We discuss some highly touted hypotheses and draw interim conclusions about what is known, and what could be done to improve the level of evidence. The complex nature of diet and its associations can be productively investigated with disease-specific studies. However, public health recommendations for normal-risk individuals regarding diet and gastrointestinal cancer should probably emphasize the importance of eating for overall health, rather than eating specific foods to reduce risk for specific cancers.
PMCID: PMC4414068  PMID: 25680671
12.  Association between tobacco use and the upper gastrointestinal microbiome among Chinese men 
Cancer causes & control : CCC  2015;26(4):581-588.
Tobacco causes many adverse health conditions and may alter the upper gastrointestinal (UGI) microbiome. However, the few studies that studied the association between tobacco use and the microbiome were small and underpowered. Therefore, we investigated the association between tobacco use and the UGI microbiome in Chinese men.
We included 278 men who underwent esophageal cancer screening in Henan Province, China. Men were categorized as current, former, or never smokers from questionnaire data. UGI tract bacterial cells were characterized using the Human Oral Microbial Identification Microarray. Counts of unique bacterial species and genera estimated alpha diversity. For beta diversity, principal coordinate (PCoA) vectors were generated from an unweighted UniFrac distance matrix. Polytomous logistic regression models were used for most analyses.
Of the 278 men in this study, 46.8% were current smokers and 12.6% were former smokers. Current smokers tended to have increased alpha diversity (mean: 42.3 species) compared to never smokers (mean: 38.9 species). For a 10 species increase, the odds ratio (OR) for current smoking was 1.29 (95% CI: 1.04–1.62). Beta diversity was also associated with current smoking. The first two PCoA vectors were strongly associated with current smoking (PCoA1 OR 0.66; 95% CI: 0.51–0.87; PCoA2 OR 0.73; 95% CI: 0.56–0.95). Furthermore, Dialister invisus and Megasphaera micronuciformis were more commonly detected in current smokers than in never smokers.
Current smoking was associated with both alpha and beta diversity in the UGI tract. Future work should consider how the UGI microbiome is associated with smoking related diseases.
PMCID: PMC4852095  PMID: 25701246
China; microbiome; tobacco; upper gastrointestinal tract
13.  Long-Term Follow-Up of a Community Assignment, One-Time Endoscopic Screening Study of Esophageal Cancer in China 
Journal of Clinical Oncology  2015;33(17):1951-1957.
There are no global screening recommendations for esophageal squamous cell carcinoma (ESCC). Endoscopic screening has been investigated in areas of high incidence in China since the 1970s. This study aimed to evaluate whether an endoscopic screening and intervention program could reduce mortality caused by ESCC.
Residents age 40 to 69 years were recruited from communities with high rates of ESCC. Fourteen villages were selected as the intervention communities. Ten villages not geographically adjacent to intervention villages were selected for comparison. Participants in the intervention group were screened once by endoscopy with Lugol's iodine staining, and those with dysplasia or occult cancer were treated. All intervention participants and a sample consisting of one tenth of the control group completed questionnaires. We compared cumulative ESCC incidence and mortality between the two groups.
Three thousand three hundred nineteen volunteers (48.62%) from an eligible population of 6,827 were screened in the intervention group. Seven hundred ninety-seven volunteers from an eligible population of 6,200 in the control group were interviewed. Six hundred fifty-two incident and 542 fatal ESCCs were identified during the 10-year follow-up. A reduction in cumulative mortality in the intervention group versus the control group was apparent (3.35% v 5.05%, respectively; P < .001). Furthermore, the intervention group had a significantly lower cumulative incidence of ESCC versus the control group (4.17% v 5.92%, respectively; P < .001).
We showed that endoscopic screening and intervention significantly reduced mortality caused by esophageal cancer. Detection and treatment of preneoplastic lesions also led to a reduction in the incidence of this highly fatal cancer.
PMCID: PMC4881309  PMID: 25940715
14.  Association Between Circulating Levels of Sex Steroid Hormones and Barrett's Esophagus in Men: a Case–Control Analysis 
Background & Aims
Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, and the ratio is increasing; approximately 7 men are diagnosed with malignancy for every woman, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population.
We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 173 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by ELISA. We also calculated free estradiol, free testosterone and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index (BMI; kg/m2), heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation).
Levels of free testosterone and free DHT were positively associated with BE risk; patients in the highest quartile for these hormones were most likely to have BE (for free testosterone, OR=5.36; 95% CI, 2.21–13.03; P=0.0002 and for free DHT, OR=4.25, 95% CI, 1.87–9.66; P=.001). Level of estrone sulfate was inversely associated with BE risk (P for trend=.02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI.
In an analysis of men, levels of free testosterone and free DHT were significantly associated with risk of BE.
PMCID: PMC4339666  PMID: 25158929
BEEDS; SHBG; gonadal steroid hormones; esophageal neoplasms; cancer risk
15.  Beta-Diversity Metrics of the Upper Digestive Tract Microbiome are Associated with Body Mass Index 
Obesity (Silver Spring, Md.)  2015;23(4):862-869.
Studies of the fecal microbiome have implicated the gut microbiota in obesity, but few studies examined the microbial diversity at other sites. We explored the association between obesity and the upper gastrointestinal (UGI) microbial diversity.
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).
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=0.0132 and p=0.0280, respectively). Moreover, beta diversity, assessed by cluster membership (3 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).
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.
PMCID: PMC4380747  PMID: 25755147
beta-diversity; body mass index; Chinese; microbiome; obesity; upper gastrointestinal tract
16.  Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers 
PLoS ONE  2016;11(3):e0150962.
Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo-linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12–0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma.
PMCID: PMC4788441  PMID: 26967509
17.  Risk of Gastrointestinal Cancers among Patients with Appendectomy: A Large-Scale Swedish Register-Based Cohort Study during 1970-2009 
PLoS ONE  2016;11(3):e0151262.
Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis. Therefore, we conducted a nationwide register-based cohort study in Sweden to investigate whether appendectomy is associated with altered risks of gastrointestinal cancers.
A population-based cohort study was conducted using the Swedish national registries, including 480,382 eligible patients followed during the period of 1970–2009 for the occurrence of site-specific gastrointestinal cancer (esophageal/gastric/colon/rectal cancer). Outcome and censoring information was collected by linkage to health and demography registers. We examined the incidence of appendectomy in Sweden using data from 1987–2009. We also calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) to estimate the relative gastrointestinal cancer risk through comparison to the general population.
We noted an overall decrease in the age-standardized incidence of appendectomy among the entire Swedish population from 189.3 to 105.6 per 100,000 individuals between 1987 and 2009. Grouped by different discharge diagnosis, acute appendicitis, incidental appendectomy, and entirely negative appendectomy continuously decreased over the study period, while the perforation ratio (18%–23%) stayed relatively constant. Compared to the general population, no excess cancer risk was observed for gastrointestinal cancers under study with the exception of a marginally elevated risk for esophageal adenocarcinoma (SIR 1.32, 95% CI 1.09–1.58).
In Sweden, the incidence of appendectomy and acute appendicitis has decreased during 1987–2009. No excess gastrointestinal cancer risks were observed among these appendectomized patients, with the possible exception of esophageal adenocarcinoma.
PMCID: PMC4784880  PMID: 26959234
18.  Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China 
Scientific Reports  2016;6:22619.
Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984–1991, 2445 subjects aged 40–69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow-up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases.
PMCID: PMC4778051  PMID: 26939909
19.  Multimorbidity: Epidemiology and Risk Factors in the Golestan Cohort Study, Iran 
Medicine  2016;95(7):e2756.
Advances in medicine and health policy have resulted in growing of older population, with a concurrent rise in multimorbidity, particularly in Iran, as a country transitioning to a western lifestyle, and in which the percent of the population over the age of 60 years is increasing. This study aims to assess multimorbidity and the associated risk factors in Iran.
We used data from 50,045 participants (age 40–75 y) in the Golestan Cohort Study, including data on demographics, lifestyle habits, socioeconomic status, and anthropometric indices. Multimorbidity was defined as the presence of 2 or more out of 8 self-reported chronic conditions, including cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, gastroesophageal reflux disease, tuberculosis, and cancer. Multivariate logistic regression models were used to examine the associations between multiple different factors and the risk factors.
Multimorbidity prevalence was 19.4%, with the most common chronic diseases being gastroesophageal reflux disease (76.7%), cardiovascular diseases (72.7%), diabetes (25.3%), and chronic obstructive pulmonary disease (21.9%). The odds of multimorbidity was 2.56-fold higher at the age of >60 years compared with that at <50 years (P < 0.001), and 2.11-fold higher in women than in men (P < 0.001). Other factors associated with higher risk of multimorbidity included non-Turkmen ethnicity, low education, unemployment, low socioeconomic status, physical inactivity, overweight, obesity, former smoking, opium and alcohol use, and poor oral health.
Apart from advanced age and female sex, the most important potentially modifiable lifestyle factors, including excess body weight and opium use, and opium user, are associated with multimorbidity. Policies aiming at controlling multimorbidity will require a multidimensional approach to reduce modifiable risk factors in the younger population in developing countries alongside adopting efficient strategies to improve life quality in the older population.
PMCID: PMC4998618  PMID: 26886618
20.  Association between C-reactive protein, incident liver cancer and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: a nested case-control study 
C-reactive protein is a marker of systemic inflammation that has been associated with the incidence and prognosis for a number of different cancers. Recent data suggests that C-reactive protein may be a prognostic factor for liver cancer and cirrhosis. However, few long-term studies are available.
We prospectively examined associations between serum C-reactive protein and subsequent risk of liver cancer incidence or chronic liver disease mortality in a nested case-control study performed in the Linxian Nutrition Intervention Trials cohort. Baseline serum C-reactive protein was measured for 220 incident liver cancer cases, 276 participants who died of chronic liver disease, and 1018 age-, sex-, and trial-matched controls. Unconditional logistical regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI).
Compared to the lowest quartile, subjects in the fourth quartile of serum C-reactive protein had a higher risk of liver cancer incidence (OR=1.63, 95% CI: 1.06–2.51), with a significant p-trend across quartiles (P=0.01). The association with liver cancer was only significant among men (Q4 vs Q1, OR=2.00, 1.10–3.62), but not among women (Q4 vs Q1, OR=1.15, 0.60–2.22). For chronic liver disease deaths, the corresponding risk estimate in men and women was 2.95(1.90–4.57), with a monotonic trend (P<0.001).
Higher serum C-reactive protein concentrations at baseline were associated with subsequent incidence of liver cancer and death from chronic liver disease.
Our findings suggest that levels of systemic inflammation may serve as a long-term marker of liver cancer and liver disease.
PMCID: PMC4323937  PMID: 25613115
C-reactive protein; Liver cancer; Chronic liver disease; Nested case-control study
21.  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, Zhaoming | Zhu, Bin | Zhang, Mingfeng | Parikh, Hemang | Jia, Jinping | Chung, Charles C. | Sampson, Joshua N. | Hoskins, Jason W. | Hutchinson, Amy | Burdette, Laurie | Ibrahim, Abdisamad | Hautman, Christopher | Raj, Preethi S. | Abnet, Christian C. | Adjei, Andrew A. | Ahlbom, Anders | Albanes, Demetrius | Allen, Naomi E. | Ambrosone, Christine B. | Aldrich, Melinda | Amiano, Pilar | Amos, Christopher | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Arici, Cecilia | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Beane Freeman, Laura E. | Berg, Christine D. | Berndt, Sonja I. | Bertazzi, Pier Alberto | Biritwum, Richard B. | Black, Amanda | Blot, William | Boeing, Heiner | Boffetta, Paolo | Bolton, Kelly | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brennan, Paul | Brinton, Louise A. | Brotzman, Michelle | Bueno-de-Mesquita, H. Bas | Buring, Julie E. | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Cao, Guangwen | Caporaso, Neil E. | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chang, Gee-Chen | Chang, I-Shou | Chang-Claude, Jenny | Che, Xu | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chung-Hsing | Chen, Constance | Chen, Kuan-Yu | Chen, Yuh-Min | Chokkalingam, Anand P. | Chu, Lisa W. | Clavel-Chapelon, Francoise | Colditz, Graham A. | Colt, Joanne S. | Conti, David | Cook, Michael B. | Cortessis, Victoria K. | Crawford, E. David | Cussenot, Olivier | Davis, Faith G. | De Vivo, Immaculata | Deng, Xiang | Ding, Ti | Dinney, Colin P. | Di Stefano, Anna Luisa | Diver, W. Ryan | Duell, Eric J. | Elena, Joanne W. | Fan, Jin-Hu | Feigelson, Heather Spencer | Feychting, Maria | Figueroa, Jonine D. | Flanagan, Adrienne M. | Fraumeni, Joseph F. | Freedman, Neal D. | Fridley, Brooke L. | Fuchs, Charles S. | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Garcia-Closas, Reina | Gastier-Foster, Julie M. | Gaziano, J. Michael | Gerhard, Daniela S. | Giffen, Carol A. | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gonzalez, Carlos | Gorlick, Richard | Greene, Mark H. | Gross, Myron | Grossman, H. Barton | Grubb, Robert | Gu, Jian | Guan, Peng | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Hartge, Patricia | Hattinger, Claudia | Hayes, Richard B. | He, Qincheng | Helman, Lee | Henderson, Brian E. | Henriksson, Roger | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hosgood, H. Dean | Hsiao, Chin-Fu | Hsing, Ann W. | Hsiung, Chao Agnes | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Hunter, David J. | Inskip, Peter D. | Ito, Hidemi | Jacobs, Eric J. | Jacobs, Kevin B. | Jenab, Mazda | Ji, Bu-Tian | Johansen, Christoffer | Johansson, Mattias | Johnson, Alison | Kaaks, Rudolf | Kamat, Ashish M. | Kamineni, Aruna | Karagas, Margaret | Khanna, Chand | Khaw, Kay-Tee | Kim, Christopher | Kim, In-Sam | Kim, Jin Hee | Kim, Yeul Hong | Kim, Young-Chul | Kim, Young Tae | Kang, Chang Hyun | Jung, Yoo Jin | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert | Kogevinas, Manolis | Koh, Woon-Puay | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kratz, Christian P. | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kurucu, Nilgun | Lan, Qing | Lathrop, Mark | Lau, Ching C. | Lecanda, Fernando | Lee, Kyoung-Mu | Lee, Maxwell P. | Le Marchand, Loic | Lerner, Seth P. | Li, Donghui | Liao, Linda M. | Lim, Wei-Yen | Lin, Dongxin | Lin, Jie | Lindstrom, Sara | Linet, Martha S. | Lissowska, Jolanta | Liu, Jianjun | Ljungberg, Börje | Lloreta, Josep | Lu, Daru | Ma, Jing | Malats, Nuria | Mannisto, Satu | Marina, Neyssa | Mastrangelo, Giuseppe | Matsuo, Keitaro | McGlynn, Katherine A. | McKean-Cowdin, Roberta | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Meltzer, Paul S. | Mensah, James E. | Miao, Xiaoping | Michaud, Dominique S. | Mondul, Alison M. | Moore, Lee E. | Muir, Kenneth | Niwa, Shelley | Olson, Sara H. | Orr, Nick | Panico, Salvatore | Park, Jae Yong | Patel, Alpa V. | Patino-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Pu, Xia | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Riboli, Elio | Risch, Harvey A. | Rodabough, Rebecca J. | Rothman, Nathaniel | Ruder, Avima M. | Ryu, Jeong-Seon | Sanson, Marc | Schned, Alan | Schumacher, Fredrick R. | Schwartz, Ann G. | Schwartz, Kendra L. | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Severi, Gianluca | Shen, Hongbing | Shen, Min | Shete, Sanjay | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesumaga, Luis | Sierri, Sabina | Loon Sihoe, Alan Dart | Silverman, Debra T. | Simon, Matthias | Southey, Melissa C. | Spector, Logan | Spitz, Margaret | Stampfer, Meir | Stattin, Par | Stern, Mariana C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael Z. | Stram, Daniel O. | Strom, Sara S. | Su, Wu-Chou | Sund, Malin | Sung, Sook Whan | Swerdlow, Anthony | Tan, Wen | Tanaka, Hideo | Tang, Wei | Tang, Ze-Zhang | Tardon, Adonina | Tay, Evelyn | Taylor, Philip R. | Tettey, Yao | Thomas, David M. | Tirabosco, Roberto | Tjonneland, Anne | Tobias, Geoffrey S. | Toro, Jorge R. | Travis, Ruth C. | Trichopoulos, Dimitrios | Troisi, Rebecca | Truelove, Ann | Tsai, Ying-Huang | Tucker, Margaret A. | Tumino, Rosario | Van Den Berg, David | Van Den Eeden, Stephen K. | Vermeulen, Roel | Vineis, Paolo | Visvanathan, Kala | Vogel, Ulla | Wang, Chaoyu | Wang, Chengfeng | Wang, Junwen | Wang, Sophia S. | Weiderpass, Elisabete | Weinstein, Stephanie J. | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolk, Alicja | Wolpin, Brian M. | Wong, Maria Pik | Wrensch, Margaret | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Yang, Hannah P. | Yang, Pan-Chyr | Yatabe, Yasushi | Ye, Yuanqing | Yeboah, Edward D. | Yin, Zhihua | Ying, Chen | Yu, Chong-Jen | Yu, Kai | Yuan, Jian-Min | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Mirabello, Lisa | Savage, Sharon A. | Kraft, Peter | Chanock, Stephen J. | Yeager, Meredith | Landi, Maria Terese | Shi, Jianxin | Chatterjee, Nilanjan | Amundadottir, Laufey T.
Human Molecular Genetics  2014;23(24):6616-6633.
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 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 (association analysis based on subsets) 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: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). 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.
PMCID: PMC4240198  PMID: 25027329
22.  The microbiome quality control project: baseline study design and future directions 
Genome Biology  2015;16:276.
Microbiome research has grown exponentially over the past several years, but studies have been difficult to reproduce across investigations. Relevant variation in measurements between laboratories, from a variety of sources, has not been systematically assessed. This is coupled with a growing concern in the scientific community about the lack of reproducibility in biomedical research. The Microbiome Quality Control project (MBQC) was initiated to identify sources of variation in microbiome studies, to quantify their magnitudes, and to assess the design and utility of different positive and negative control strategies. Here we report on the first MBQC baseline study project and workshop.
PMCID: PMC4674991  PMID: 26653756
23.  Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study 
Hepatology (Baltimore, Md.)  2014;60(6):1963-1971.
Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori (H. pylori) proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.
We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. H. pylori seropositivity was defined as those positive to ≥4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors.
Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of Ampula of vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95%CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above one were observed for many of the investigated antigens, although most of these associations were not statistically significant.
Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence risk of biliary tract cancer.
PMCID: PMC4216769  PMID: 24797247
Helicobacter pylori; multiplex serology; liver cancer; biliary cancer
24.  Index-Based Dietary Patterns and Risk of Esophageal and Gastric Cancer in a Large Cohort Study 
Background & Aims
Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers.
We analyzed data from 494,968 participants in the National Institutes of Health (NIH)-AARP Diet and Health study, in which AARP members (51–70 y old) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index.
During the follow-up period (1995–2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest: hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.31–0.86; Ptrend=.001) and EAC (HR, 0.75; 95% CI, 0.57–0.98; Ptrend=.01). We observed an inverse association between ESCC, but not EAC, and higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not significantly associated with gastric cardia or noncardia adenocarcinomas.
Using data collected from 1995 through 2006 from the NIH-AARP Diet and Health Study, HEI-2005 and aMED scores were inversely associated with risk for esophageal cancers—particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers.
PMCID: PMC3758458  PMID: 23591281
food habits; esophageal neoplasms; stomach neoplasms
25.  Oesophageal squamous cell carcinoma in high-risk Chinese populations: Possible role for vascular epithelial growth factor A 
Mechanisms involved in wound healing play some role in carcinogenesis in multiple organs, likely by creating a chronic inflammatory milieu. This study sought to assess the role of genetic markers in selected inflammation-related genes involved in wound healing (interleukin (IL)-1a, IL-1b, IL-1 Receptor type I (IL-1Ra), IL-1 Receptor type II (IL-1Rb), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor superfamily member (TNFRSF)1A, nuclear factor kappa beta (NF-kB)1, NF-kB2, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, hypoxia induced factor (HIF)-1α, vascular endothelial growth factor (VEGF)A and P-53) in risk to oesophageal squamous cell carcinoma (OSCC).
We genotyped 125 tag single nucleotide polymorphism (SNP)s in 410 cases and 377 age and sex matched disease-free individuals from Nutritional Intervention Trial (NIT) cohort, and 546 cases and 556 controls individually matched for age, sex and neighbourhood from Shanxi case–control study, both conducted in high-risk areas of north-central China (1985–2007). Cox proportional-hazard models and conditional logistic regression models were used for SNPs analyses for NIT and Shanxi, respectively. Fisher's inverse test statistics were used to obtain gene-level significance.
Multiple SNPs were significantly associated with OSCC in both studies, however, none retained their significance after a conservative Bonferroni adjustment. Empiric p-values for tag SNPs in VEGFA in NIT were highly concentrated in the lower tail of the distribution, suggesting this gene may be influencing risk. Permutation tests confirmed the significance of this pattern. At the gene level, VEGFA yielded an empiric significance (P = 0.027) in NIT. We also observed some evidence for interaction between environmental factors and some VEGFA tag SNPs.
Our finding adds further evidence for a potential role for markers in the VEGFA gene in the development and progression of early precancerous lesions of oesophagus.
PMCID: PMC4363989  PMID: 25172294
Oesophageal squamous; cell carcinoma; Inflammation; Wound-healing; Genetic marker; Genetics; Inflammation-related events; Vascular endothelial growth factor A; VEGFA

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