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1. Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Author

Dong, Jing, Levine, David M., Buas, Matthew F., Zhang, Rui, Onstad, Lynn, Fitzgerald, Rebecca C., Corley, Douglas A., Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Reid, Brian J., Iyer, Prasad G., Risch, Harvey A., Caldas, Carlos, Caldas, Isabel, Pharoah, Paul D., Liu, Geoffrey, Gammon, Marilie D., Chow, Wong-Ho, Bernstein, Leslie, Bird, Nigel C., Ye, Weimin, Wu, Anna H., Anderson, Lesley A., MacGregor, Stuart, Whiteman, David C., Vaughan, Thomas L., and Thrift, Aaron P.

Published
2018
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2. Determining Risk of Barrett’s Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants

Author

Dong, Jing, Buas, Matthew F., Gharahkhani, Puya, Kendall, Bradley J., Onstad, Lynn, Zhao, Shanshan, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Bernstein, Leslie, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., Iyer, Prasad G., Reid, Brian J., Hardie, Laura J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Fitzgerald, Rebecca C., Whiteman, David C., Vaughan, Thomas L., and Thrift, Aaron P.

Published
2018
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3. Supplementary Figure legends from A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Author

Dai, James Y., primary, de Dieu Tapsoba, Jean, primary, Buas, Matthew F., primary, Onstad, Lynn E., primary, Levine, David M., primary, Risch, Harvey A., primary, Chow, Wong-Ho, primary, Bernstein, Leslie, primary, Ye, Weimin, primary, Lagergren, Jesper, primary, Bird, Nigel C., primary, Corley, Douglas A., primary, Shaheen, Nicholas J., primary, Wu, Anna H., primary, Reid, Brian J., primary, Hardie, Laura J., primary, Whiteman, David C., primary, and Vaughan, Thomas L., primary

Published
2023
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4. Supplementary figure 1 from A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Author

Dai, James Y., primary, de Dieu Tapsoba, Jean, primary, Buas, Matthew F., primary, Onstad, Lynn E., primary, Levine, David M., primary, Risch, Harvey A., primary, Chow, Wong-Ho, primary, Bernstein, Leslie, primary, Ye, Weimin, primary, Lagergren, Jesper, primary, Bird, Nigel C., primary, Corley, Douglas A., primary, Shaheen, Nicholas J., primary, Wu, Anna H., primary, Reid, Brian J., primary, Hardie, Laura J., primary, Whiteman, David C., primary, and Vaughan, Thomas L., primary

Published
2023
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5. Data from Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk

Author

Lee, Eunjung, primary, Stram, Daniel O., primary, Ek, Weronica E., primary, Onstad, Lynn E., primary, MacGregor, Stuart, primary, Gharahkhani, Puya, primary, Ye, Weimin, primary, Lagergren, Jesper, primary, Shaheen, Nicholas J., primary, Murray, Liam J., primary, Hardie, Laura J., primary, Gammon, Marilie D., primary, Chow, Wong-Ho, primary, Risch, Harvey A., primary, Corley, Douglas A., primary, Levine, David M., primary, Whiteman, David C., primary, Bernstein, Leslie, primary, Bird, Nigel C., primary, Vaughan, Thomas L., primary, and Wu, Anna H., primary

Published
2023
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6. Data from A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Author

Dai, James Y., primary, de Dieu Tapsoba, Jean, primary, Buas, Matthew F., primary, Onstad, Lynn E., primary, Levine, David M., primary, Risch, Harvey A., primary, Chow, Wong-Ho, primary, Bernstein, Leslie, primary, Ye, Weimin, primary, Lagergren, Jesper, primary, Bird, Nigel C., primary, Corley, Douglas A., primary, Shaheen, Nicholas J., primary, Wu, Anna H., primary, Reid, Brian J., primary, Hardie, Laura J., primary, Whiteman, David C., primary, and Vaughan, Thomas L., primary

Published
2023
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8. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, R G Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H M, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, and Schumacher, Johannes

Published
2016
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9. Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

Author

Thrift, Aaron P., Risch, Harvey A., Onstad, Lynn, Shaheen, Nicholas J., Casson, Alan G., Bernstein, Leslie, Corley, Douglas A., Levine, David M., Chow, Wong–Ho, Reid, Brian J., Romero, Yvonne, Hardie, Laura J., Liu, Geoffrey, Wu, Anna H., Bird, Nigel C., Gammon, Marilie D., Ye, Weimin, Whiteman, David C., and Vaughan, Thomas L.

Published
2014
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10. Germline variation in inflammation-related pathways and risk of Barrettʼs oesophagus and oesophageal adenocarcinoma

Author

Buas, Matthew F, He, Qianchuan, Johnson, Lisa G, Onstad, Lynn, Levine, David M, Thrift, Aaron P, Gharahkhani, Puya, Palles, Claire, Lagergren, Jesper, Fitzgerald, Rebecca C, Ye, Weimin, Caldas, Carlos, Bird, Nigel C, Shaheen, Nicholas J, Bernstein, Leslie, Gammon, Marilie D, Wu, Anna H, Hardie, Laura J, Pharoah, Paul D, Liu, Geoffrey, Iyer, Prassad, Corley, Douglas A, Risch, Harvey A, Chow, Wong-Ho, Prenen, Hans, Chegwidden, Laura, Love, Sharon, Attwood, Stephen, Moayyedi, Paul, MacDonald, David, Harrison, Rebecca, Watson, Peter, Barr, Hugh, deCaestecker, John, Tomlinson, Ian, Jankowski, Janusz, Whiteman, David C, MacGregor, Stuart, Vaughan, Thomas L, and Madeleine, Margaret M

Published
2017
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11. Polymorphisms in genes in the androgen pathway and risk of Barrettʼs esophagus and esophageal adenocarcinoma

Author

Ek, Weronica E., Lagergren, Katarina, Cook, Michael, Wu, Anna H., Abnet, Christian C., Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A., Shaheen, Nicholas J., Bird, Nigel C., Corley, Douglas A., Hardie, Laura J., Fitzgerald, Rebecca C., Gammon, Marilie D., Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L., MacGregor, Stuart, Whiteman, David C., Westberg, Lars, and Lagergren, Jesper

Published
2016
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12. Obesity and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: A Mendelian Randomization Study

Author

Thrift, Aaron P., Shaheen, Nicholas J., Gammon, Marilie D., Bernstein, Leslie, Reid, Brian J., Onstad, Lynn, Risch, Harvey A., Liu, Geoffrey, Bird, Nigel C., Wu, Anna H., Corley, Douglas A., Romero, Yvonne, Chanock, Stephen J., Chow, Wong-Ho, Casson, Alan G., Levine, David M., Zhang, Rui, Ek, Weronica E., MacGregor, Stuart, Ye, Weimin, Hardie, Laura J., Vaughan, Thomas L., and Whiteman, David C.

Published
2014
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13. Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma

Author

Buas, Matthew F., Levine, David M., Makar, Karen W., Utsugi, Heidi, Onstad, Lynn, Li, Xiaohong, Galipeau, Patricia C., Shaheen, Nicholas J., Hardie, Laura J., Romero, Yvonne, Bernstein, Leslie, Gammon, Marilie D., Casson, Alan G., Bird, Nigel C., Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Corley, Douglas A., Blount, Patricia L., Fitzgerald, Rebecca C., Whiteman, David C., Wu, Anna H., Reid, Brian J., and Vaughan, Thomas L.

Published
2014
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14. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Ong, Jue-Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Liyanage, Upekha, Dusingize, Jean-Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C. [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O’Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P. [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M. [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/68, 45/43, article, 692/699/67/2195, 692/4028/67/2324
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Published
2021
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15. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, other, and, Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, and other, and

Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Published
2021

17. Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett’s Esophagus, and Gastroesophageal Reflux

Author

Ek, Weronica E., Levine, David M., D’Amato, Mauro, Pedersen, Nancy L., Magnusson, Patrik K. E., Bresso, Francesca, Onstad, Lynn E., Schmidt, Peter T., Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J., Gammon, Marilie D., Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G., Risch, Harvey A., Shaheen, Nicholas J., Bird, Nigel C., Reid, Brian J., Corley, Douglas A., Hardie, Laura J., Ye, Weimin, Wu, Anna H., Zucchelli, Marco, Spector, Tim D., Hysi, Pirro, Vaughan, Thomas L., Whiteman, David C., and MacGregor, Stuart

Published
2013
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20. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue-Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Gockel, Ines, Thieme, René, Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Whiteman, David C., MacGregor, Stuart, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H. [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M. [0000-0003-4483-1888], Böhmer, Anne C. [0000-0002-5716-786X], Fitzgerald, Rebecca C. [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/1504/1477, 631/208/205/2138, 45/43, article, 38/39, 631/208/68, 692/699/1503/1476/196, health care economics and organizations, humanities, digestive system diseases
Abstract

Funder: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute he California Tobacco Related Research Program (3RT-0122; and; 10RT-0251) Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C, Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

Published
2019

24. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author

Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz

Subjects
Risk, Esophageal Neoplasms, LD, linkage disequilibrium, ASE, allele-specific expression, eQTL, expression quantitative trait locus, Polymorphism, Single Nucleotide, Barrett Esophagus, Intestinal Metaplasia, Full Report: Basic and Translational—Alimentary Tract, BE, Barrett’s esophagus, Humans, Genetic Predisposition to Disease, EAC, esophageal adenocarcinoma, EAC, GWAS, genome-wide association study, Original Research, Cancer, BEACON, Barrett's and Esophageal Adenocarcinoma Consortium, Gastroenterology, PC, principal component, SNP, single nucleotide polymorphism, A300, CI, confidence interval, OR, odds ratio, Growth Differentiation Factors, Susceptibility, Bone Morphogenetic Proteins, TCGA, The Cancer Genome Atlas, Human medicine, T-Box Domain Proteins, Genome-Wide Association Study
Abstract

Background & Aims\ud Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.\ud \ud Methods\ud We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.\ud \ud Results\ud We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).\ud \ud Conclusions\ud We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Published
2015
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25. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Author

van Dam, Pieter-Jan, van der Stok, Eric P., Teuwen, Laure-Anne, Van den Eynden, Gert G., Illemann, Martin, Frentzas, Sophia, Majeed, Ali W., Eefsen, Rikke L., van den Braak, Robert R. J. Coebergh, Lazaris, Anthoula, Fernandez, Maria Celia, Galjart, Boris, Laerum, Ole Didrik, Rayes, Roni, Grunhagen, Dirk J., Van de Paer, Michelle, Sucaet, Yves, Mudhar, Hardeep Singh, Schvimer, Michael, Nyström, Hanna, Kockx, Mark, Bird, Nigel C., Vidal-Vanaclocha, Fernando, Metrakos, Peter, Simoneau, Eve, Verhoef, Cornelis, Dirix, Luc Y., Van Laere, Steven, Gao, Zu-hua, Brodt, Pnina, Reynolds, Andrew R., Vermeulen, Peter B., van Dam, Pieter-Jan, van der Stok, Eric P., Teuwen, Laure-Anne, Van den Eynden, Gert G., Illemann, Martin, Frentzas, Sophia, Majeed, Ali W., Eefsen, Rikke L., van den Braak, Robert R. J. Coebergh, Lazaris, Anthoula, Fernandez, Maria Celia, Galjart, Boris, Laerum, Ole Didrik, Rayes, Roni, Grunhagen, Dirk J., Van de Paer, Michelle, Sucaet, Yves, Mudhar, Hardeep Singh, Schvimer, Michael, Nyström, Hanna, Kockx, Mark, Bird, Nigel C., Vidal-Vanaclocha, Fernando, Metrakos, Peter, Simoneau, Eve, Verhoef, Cornelis, Dirix, Luc Y., Van Laere, Steven, Gao, Zu-hua, Brodt, Pnina, Reynolds, Andrew R., and Vermeulen, Peter B.

Abstract

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Published
2017
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26. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes

Abstract

SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc

Published
2017

27. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Author

Van Dam, Pieter Jan, Van Der Stok, Eric P., Teuwen, Laure Anne, Van Den Eynden, Gert G., Illemann, Martin, Frentzas, Sophia, Majeed, Ali W., Eefsen, Rikke L., Coebergh Van Den Braak, Robert R.J., Lazaris, Anthoula, Fernandez, Maria Celia, Galjart, Boris, Laerum, Ole Didrik, Rayes, Roni, Grünhagen, Dirk J., Van De Paer, Michelle, Sucaet, Yves, Mudhar, Hardeep Singh, Schvimer, Michael, Nyström, Hanna, Kockx, Mark, Bird, Nigel C., Vidal-Vanaclocha, Fernando, Metrakos, Peter, Simoneau, Eve, Verhoef, Cornelis, Dirix, Luc Y., Van Laere, Steven, Gao, Zu Hua, Brodt, Pnina, Reynolds, Andrew R., Vermeulen, Peter B., Van Dam, Pieter Jan, Van Der Stok, Eric P., Teuwen, Laure Anne, Van Den Eynden, Gert G., Illemann, Martin, Frentzas, Sophia, Majeed, Ali W., Eefsen, Rikke L., Coebergh Van Den Braak, Robert R.J., Lazaris, Anthoula, Fernandez, Maria Celia, Galjart, Boris, Laerum, Ole Didrik, Rayes, Roni, Grünhagen, Dirk J., Van De Paer, Michelle, Sucaet, Yves, Mudhar, Hardeep Singh, Schvimer, Michael, Nyström, Hanna, Kockx, Mark, Bird, Nigel C., Vidal-Vanaclocha, Fernando, Metrakos, Peter, Simoneau, Eve, Verhoef, Cornelis, Dirix, Luc Y., Van Laere, Steven, Gao, Zu Hua, Brodt, Pnina, Reynolds, Andrew R., and Vermeulen, Peter B.

Abstract

Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Published
2017

28. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Author

van Dam, Pieter-Jan, primary, van der Stok, Eric P, additional, Teuwen, Laure-Anne, additional, Van den Eynden, Gert G, additional, Illemann, Martin, additional, Frentzas, Sophia, additional, Majeed, Ali W, additional, Eefsen, Rikke L, additional, Coebergh van den Braak, Robert R J, additional, Lazaris, Anthoula, additional, Fernandez, Maria Celia, additional, Galjart, Boris, additional, Laerum, Ole Didrik, additional, Rayes, Roni, additional, Grünhagen, Dirk J, additional, Van de paer, Michelle, additional, Sucaet, Yves, additional, Mudhar, Hardeep Singh, additional, Schvimer, Michael, additional, Nyström, Hanna, additional, Kockx, Mark, additional, Bird, Nigel C, additional, Vidal-Vanaclocha, Fernando, additional, Metrakos, Peter, additional, Simoneau, Eve, additional, Verhoef, Cornelis, additional, Dirix, Luc Y, additional, Van Laere, Steven, additional, Gao, Zu-hua, additional, Brodt, Pnina, additional, Reynolds, Andrew R, additional, and Vermeulen, Peter B, additional

Published
2017
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30. Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, Lagergren, Jesper, Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, and Lagergren, Jesper

Abstract

The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

Published
2016
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31. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes

Abstract

SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc

Published
2016

32. Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Author

Buas, Matthew F, primary, He, Qianchuan, additional, Johnson, Lisa G, additional, Onstad, Lynn, additional, Levine, David M, additional, Thrift, Aaron P, additional, Gharahkhani, Puya, additional, Palles, Claire, additional, Lagergren, Jesper, additional, Fitzgerald, Rebecca C, additional, Ye, Weimin, additional, Caldas, Carlos, additional, Bird, Nigel C, additional, Shaheen, Nicholas J, additional, Bernstein, Leslie, additional, Gammon, Marilie D, additional, Wu, Anna H, additional, Hardie, Laura J, additional, Pharoah, Paul D, additional, Liu, Geoffrey, additional, Iyer, Prassad, additional, Corley, Douglas A, additional, Risch, Harvey A, additional, Chow, Wong-Ho, additional, Prenen, Hans, additional, Chegwidden, Laura, additional, Love, Sharon, additional, Attwood, Stephen, additional, Moayyedi, Paul, additional, MacDonald, David, additional, Harrison, Rebecca, additional, Watson, Peter, additional, Barr, Hugh, additional, deCaestecker, John, additional, Tomlinson, Ian, additional, Jankowski, Janusz, additional, Whiteman, David C, additional, MacGregor, Stuart, additional, Vaughan, Thomas L, additional, and Madeleine, Margaret M, additional

Published
2016
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33. Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma : A Pooled Analysis from the BEACON Consortium.

Author

Lagergren, Katarina, Ek, Weronica E, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Wu, Anna H, Fitzgerald, Rebecca C, Pharoah, Paul, Caldas, Carlos, Romero, Yvonne, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David, Westberg, Lars, Nyren, Olof, Lagergren, Jesper, Lagergren, Katarina, Ek, Weronica E, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Wu, Anna H, Fitzgerald, Rebecca C, Pharoah, Paul, Caldas, Carlos, Romero, Yvonne, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David, Westberg, Lars, Nyren, Olof, and Lagergren, Jesper

Abstract

BACKGROUND: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. METHODS: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). RESULTS: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. CONCLUSION: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed., Shared first authorship

Published
2015
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34. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk.

Author

Lee, Eunjung, Stram, Daniel O, Ek, Weronica E, Onstad, Lynn E, MacGregor, Stuart, Gharahkhani, Puya, Ye, Weimin, Lagergren, Jesper, Shaheen, Nicholas J, Murray, Liam J, Hardie, Laura J, Gammon, Marilie D, Chow, Wong-Ho, Risch, Harvey A, Corley, Douglas A, Levine, David M, Whiteman, David C, Bernstein, Leslie, Bird, Nigel C, Vaughan, Thomas L, Wu, Anna H, Lee, Eunjung, Stram, Daniel O, Ek, Weronica E, Onstad, Lynn E, MacGregor, Stuart, Gharahkhani, Puya, Ye, Weimin, Lagergren, Jesper, Shaheen, Nicholas J, Murray, Liam J, Hardie, Laura J, Gammon, Marilie D, Chow, Wong-Ho, Risch, Harvey A, Corley, Douglas A, Levine, David M, Whiteman, David C, Bernstein, Leslie, Bird, Nigel C, Vaughan, Thomas L, and Wu, Anna H

Abstract

BACKGROUND: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. METHODS: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. RESULTS: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. CONCLUSIONS: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. IMPACT: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801-3. ©2015 AACR.

Published
2015
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35. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk

Author

Lee, Eunjung, primary, Stram, Daniel O., additional, Ek, Weronica E., additional, Onstad, Lynn E., additional, MacGregor, Stuart, additional, Gharahkhani, Puya, additional, Ye, Weimin, additional, Lagergren, Jesper, additional, Shaheen, Nicholas J., additional, Murray, Liam J., additional, Hardie, Laura J., additional, Gammon, Marilie D., additional, Chow, Wong-Ho, additional, Risch, Harvey A., additional, Corley, Douglas A., additional, Levine, David M., additional, Whiteman, David C., additional, Bernstein, Leslie, additional, Bird, Nigel C., additional, Vaughan, Thomas L., additional, and Wu, Anna H., additional

Published
2015
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36. A Newly Identified Susceptibility Locus nearFOXP1Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Author

Dai, James Y., primary, de Dieu Tapsoba, Jean, additional, Buas, Matthew F., additional, Onstad, Lynn E., additional, Levine, David M., additional, Risch, Harvey A., additional, Chow, Wong-Ho, additional, Bernstein, Leslie, additional, Ye, Weimin, additional, Lagergren, Jesper, additional, Bird, Nigel C., additional, Corley, Douglas A., additional, Shaheen, Nicholas J., additional, Wu, Anna H., additional, Reid, Brian J., additional, Hardie, Laura J., additional, Whiteman, David C., additional, and Vaughan, Thomas L., additional

Published
2015
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37. Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Ek, Weronica E., primary, Lagergren, Katarina, additional, Cook, Michael, additional, Wu, Anna H., additional, Abnet, Christian C., additional, Levine, David, additional, Chow, Wong-Ho, additional, Bernstein, Leslie, additional, Risch, Harvey A., additional, Shaheen, Nicholas J., additional, Bird, Nigel C., additional, Corley, Douglas A., additional, Hardie, Laura J., additional, Fitzgerald, Rebecca C., additional, Gammon, Marilie D., additional, Romero, Yvonne, additional, Liu, Geoffrey, additional, Ye, Weimin, additional, Vaughan, Thomas L., additional, MacGregor, Stuart, additional, Whiteman, David C., additional, Westberg, Lars, additional, and Lagergren, Jesper, additional

Published
2015
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38. Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium

Author

Lagergren, Katarina, primary, Ek, Weronica E., additional, Levine, David, additional, Chow, Wong-Ho, additional, Bernstein, Leslie, additional, Casson, Alan G., additional, Risch, Harvey A., additional, Shaheen, Nicholas J., additional, Bird, Nigel C., additional, Reid, Brian J., additional, Corley, Douglas A., additional, Hardie, Laura J., additional, Wu, Anna H., additional, Fitzgerald, Rebecca C., additional, Pharoah, Paul, additional, Caldas, Carlos, additional, Romero, Yvonne, additional, Vaughan, Thomas L., additional, MacGregor, Stuart, additional, Whiteman, David, additional, Westberg, Lars, additional, Nyren, Olof, additional, and Lagergren, Jesper, additional

Published
2015
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39. MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium

Author

Buas, Matthew F., primary, Onstad, Lynn, additional, Levine, David M., additional, Risch, Harvey A., additional, Chow, Wong-Ho, additional, Liu, Geoffrey, additional, Fitzgerald, Rebecca C., additional, Bernstein, Leslie, additional, Ye, Weimin, additional, Bird, Nigel C., additional, Romero, Yvonne, additional, Casson, Alan G., additional, Corley, Douglas A., additional, Shaheen, Nicholas J., additional, Wu, Anna H., additional, Gammon, Marilie D., additional, Reid, Brian J., additional, Hardie, Laura J., additional, Peters, Ulrike, additional, Whiteman, David C., additional, and Vaughan, Thomas L., additional

Published
2015
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40. Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus : a Mendelian randomization study.

Author

Thrift, Aaron P, Shaheen, Nicholas J, Gammon, Marilie D, Bernstein, Leslie, Reid, Brian J, Onstad, Lynn, Risch, Harvey A, Liu, Geoffrey, Bird, Nigel C, Wu, Anna H, Corley, Douglas A, Romero, Yvonne, Chanock, Stephen J, Chow, Wong-Ho, Casson, Alan G, Levine, David M, Zhang, Rui, Ek, Weronica E, MacGregor, Stuart, Ye, Weimin, Hardie, Laura J, Vaughan, Thomas L, Whiteman, David C, Thrift, Aaron P, Shaheen, Nicholas J, Gammon, Marilie D, Bernstein, Leslie, Reid, Brian J, Onstad, Lynn, Risch, Harvey A, Liu, Geoffrey, Bird, Nigel C, Wu, Anna H, Corley, Douglas A, Romero, Yvonne, Chanock, Stephen J, Chow, Wong-Ho, Casson, Alan G, Levine, David M, Zhang, Rui, Ek, Weronica E, MacGregor, Stuart, Ye, Weimin, Hardie, Laura J, Vaughan, Thomas L, and Whiteman, David C

Abstract

BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.

Published
2014
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41. Tumor stromal phenotypes define VEGF sensitivity-letter

Author

Van den Eynden, Gert G, Bird, Nigel C, Dirix, Luc Y, Eefsen, Rikke L, Gao, Zu-Hua, Høyer-Hansen, Gunilla, Illemann, Martin, Majeed, Ali W, Metrakos, Peter, Reynolds, Andrew R, Vainer, Ben, van Dam, Pieter-Jan, Van Laere, Steven J, Vermeulen, Peter B, Vidal-Vanaclocha, Fernando, Brodt, Pnina, Van den Eynden, Gert G, Bird, Nigel C, Dirix, Luc Y, Eefsen, Rikke L, Gao, Zu-Hua, Høyer-Hansen, Gunilla, Illemann, Martin, Majeed, Ali W, Metrakos, Peter, Reynolds, Andrew R, Vainer, Ben, van Dam, Pieter-Jan, Van Laere, Steven J, Vermeulen, Peter B, Vidal-Vanaclocha, Fernando, and Brodt, Pnina

Published
2014

42. A Pointwise Method for Identifying Biomechanical Heterogeneity of the Human Gallbladder.

Author

Wenguang Li, Bird, Nigel C., and Xiaoyu Luo

Subjects
GALLBLADDER, BIOCHEMISTRY, ACALCULOUS cholecystitis, BILE duct diseases, ULTRASONIC imaging
Abstract

Identifying the heterogeneous biomechanical property of human gallbladder (GB) walls from non-invasive measurements can have clinical significance in patient-specific modeling and acalculous biliary pain diagnosis. In this article, a pointwise method was proposed to measure the heterogeneity of ten samples of human GB during refilling. Three different points, two on the equator of GB body 90° apart and one on the apex of GB fundus, were chosen to represent the typical regions of interest. The stretches at these points were estimated from ultrasound images of the GB during the bile emptying phase based on an analytical model. The model was validated against the experimental data of a lamb GB. The material parameters at the different points were determined inversely by making use of a structure-based anisotropic constitutive model. This anisotropic model yielded much better accuracy when compared to a number of phenomenologically-based constitutive laws, as demonstrated by its significantly reduced least-square errors in stress curve fitting. The results confirmed that the human GB wall material was heterogeneous, particularly toward the apex region. Our study also suggested that non-uniform wall thickness of the GB was important in determining the material parameters, in particular, on the parameters associated with the properties of the matrix and the longitudinal fibers--the difference could be as large as 20--30%compared to that of the uniform thickness model. [ABSTRACT FROM AUTHOR]

Published
2017
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43. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux

Author

Ek, Weronica E, Levine, David M, D'Amato, Mauro, Pedersen, Nancy L, Magnusson, Patrik K E, Bresso, Francesca, Onstad, Lynn E, Schmidt, Peter T, Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J, Gammon, Marilie D, Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Ye, Weimin, Wu, Anna H, Zucchelli, Marco, Spector, Tim D, Hysi, Pirro, Vaughan, Thomas L, Whiteman, David C, MacGregor, Stuart, Ek, Weronica E, Levine, David M, D'Amato, Mauro, Pedersen, Nancy L, Magnusson, Patrik K E, Bresso, Francesca, Onstad, Lynn E, Schmidt, Peter T, Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J, Gammon, Marilie D, Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Reid, Brian J, Corley, Douglas A, Hardie, Laura J, Ye, Weimin, Wu, Anna H, Zucchelli, Marco, Spector, Tim D, Hysi, Pirro, Vaughan, Thomas L, Whiteman, David C, and MacGregor, Stuart

Abstract

BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.

Published
2013
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44. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Author

Levine, David M, Ek, Weronica E, Zhang, Rui, Liu, Xinxue, Onstad, Lynn, Sather, Cassandra, Lao-Sirieix, Pierre, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Murray, Liam J, Reid, Brian J, Chow, Wong-Ho, Risch, Harvey A, Nyrén, Olof, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Chanock, Stephen J, Harrington, Patricia, Caldas, Isabel, Debiram-Beecham, Irene, Caldas, Carlos, Hayward, Nicholas K, Pharoah, Paul D, Fitzgerald, Rebecca C, Macgregor, Stuart, Whiteman, David C, Vaughan, Thomas L, Levine, David M, Ek, Weronica E, Zhang, Rui, Liu, Xinxue, Onstad, Lynn, Sather, Cassandra, Lao-Sirieix, Pierre, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Murray, Liam J, Reid, Brian J, Chow, Wong-Ho, Risch, Harvey A, Nyrén, Olof, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Chanock, Stephen J, Harrington, Patricia, Caldas, Isabel, Debiram-Beecham, Irene, Caldas, Carlos, Hayward, Nicholas K, Pharoah, Paul D, Fitzgerald, Rebecca C, Macgregor, Stuart, Whiteman, David C, and Vaughan, Thomas L

Abstract

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

Published
2013
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45. The multifaceted role of the microenvironment in liver metastasis:biology and clinical implications

Author

Van den Eynden, Gert G, Majeed, Ali W, Illemann, Martin, Vermeulen, Peter B, Bird, Nigel C, Høyer-Hansen, Gunilla, Eefsen, Rikke Løvendahl, Reynolds, Andrew R, Brodt, Pnina, Van den Eynden, Gert G, Majeed, Ali W, Illemann, Martin, Vermeulen, Peter B, Bird, Nigel C, Høyer-Hansen, Gunilla, Eefsen, Rikke Løvendahl, Reynolds, Andrew R, and Brodt, Pnina

Abstract

The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow-derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment.

Published
2013

46. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Author

Su, Zhan, Gay, Laura J, Strange, Amy, Palles, Claire, Band, Gavin, Whiteman, David C, Lescai, Francesco, Langford, Cordelia, Nanji, Manoj, Edkins, Sarah, van der Winkel, Anouk, Levine, David, Sasieni, Peter, Bellenguez, Céline, Howarth, Kimberley, Freeman, Colin, Trudgill, Nigel, Tucker, Art T, Pirinen, Matti, Peppelenbosch, Maikel P, van der Laan, Luc J W, Kuipers, Ernst J, Drenth, Joost P H, Peters, Wilbert H, Reynolds, John V, Kelleher, Dermot P, McManus, Ross, Grabsch, Heike, Prenen, Hans, Bisschops, Raf, Krishnadath, Kausila, Siersema, Peter D, van Baal, Jantine W P M, Middleton, Mark, Petty, Russell, Gillies, Richard, Burch, Nicola, Bhandari, Pradeep, Paterson, Stuart, Edwards, Cathryn, Penman, Ian, Vaidya, Kishor, Ang, Yeng, Murray, Iain, Patel, Praful, Ye, Weimin, Mullins, Paul, Wu, Anna H, Bird, Nigel C, Dallal, Helen, Shaheen, Nicholas J, Murray, Liam J, Koss, Konrad, Bernstein, Leslie, Romero, Yvonne, Hardie, Laura J, Zhang, Rui, Winter, Helen, Corley, Douglas A, Panter, Simon, Risch, Harvey A, Reid, Brian J, Sargeant, Ian, Gammon, Marilie D, Smart, Howard, Dhar, Anjan, McMurtry, Hugh, Ali, Haythem, Liu, Geoffrey, Casson, Alan G, Chow, Wong-Ho, Rutter, Matt, Tawil, Ashref, Morris, Danielle, Nwokolo, Chuka, Isaacs, Peter, Rodgers, Colin, Ragunath, Krish, MacDonald, Chris, Haigh, Chris, Monk, David, Davies, Gareth, Wajed, Saj, Johnston, David, Gibbons, Michael, Cullen, Sue, Church, Nicholas, Langley, Ruth, Griffin, Michael, Alderson, Derek, Deloukas, Panos, Hunt, Sarah E, Gray, Emma, Dronov, Serge, Potter, Simon C, Tashakkori-Ghanbaria, Avazeh, Anderson, Mark, Brooks, Claire, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas, Trynka, Gosia, Wijmenga, Cisca, Cazier, Jean-Baptiste, Atherfold, Paul, Nicholson, Anna M, Gellatly, Nichola L, Glancy, Deborah, Cooper, Sheldon C, Cunningham, David, Lind, Tore, Hapeshi, Julie, Ferry, David, Rathbone, Barrie, Brown, Julia, Love, Sharon, Attwood, Stephen, MacGregor, Stuart, Watson, Peter, Sanders, Scott, Ek, Weronica, Harrison, Rebecca F, Moayyedi, Paul, de Caestecker, John, Barr, Hugh, Stupka, Elia, Vaughan, Thomas L, Peltonen, Leena, Spencer, Chris C A, Tomlinson, Ian, Donnelly, Peter, Jankowski, Janusz A Z, Su, Zhan, Gay, Laura J, Strange, Amy, Palles, Claire, Band, Gavin, Whiteman, David C, Lescai, Francesco, Langford, Cordelia, Nanji, Manoj, Edkins, Sarah, van der Winkel, Anouk, Levine, David, Sasieni, Peter, Bellenguez, Céline, Howarth, Kimberley, Freeman, Colin, Trudgill, Nigel, Tucker, Art T, Pirinen, Matti, Peppelenbosch, Maikel P, van der Laan, Luc J W, Kuipers, Ernst J, Drenth, Joost P H, Peters, Wilbert H, Reynolds, John V, Kelleher, Dermot P, McManus, Ross, Grabsch, Heike, Prenen, Hans, Bisschops, Raf, Krishnadath, Kausila, Siersema, Peter D, van Baal, Jantine W P M, Middleton, Mark, Petty, Russell, Gillies, Richard, Burch, Nicola, Bhandari, Pradeep, Paterson, Stuart, Edwards, Cathryn, Penman, Ian, Vaidya, Kishor, Ang, Yeng, Murray, Iain, Patel, Praful, Ye, Weimin, Mullins, Paul, Wu, Anna H, Bird, Nigel C, Dallal, Helen, Shaheen, Nicholas J, Murray, Liam J, Koss, Konrad, Bernstein, Leslie, Romero, Yvonne, Hardie, Laura J, Zhang, Rui, Winter, Helen, Corley, Douglas A, Panter, Simon, Risch, Harvey A, Reid, Brian J, Sargeant, Ian, Gammon, Marilie D, Smart, Howard, Dhar, Anjan, McMurtry, Hugh, Ali, Haythem, Liu, Geoffrey, Casson, Alan G, Chow, Wong-Ho, Rutter, Matt, Tawil, Ashref, Morris, Danielle, Nwokolo, Chuka, Isaacs, Peter, Rodgers, Colin, Ragunath, Krish, MacDonald, Chris, Haigh, Chris, Monk, David, Davies, Gareth, Wajed, Saj, Johnston, David, Gibbons, Michael, Cullen, Sue, Church, Nicholas, Langley, Ruth, Griffin, Michael, Alderson, Derek, Deloukas, Panos, Hunt, Sarah E, Gray, Emma, Dronov, Serge, Potter, Simon C, Tashakkori-Ghanbaria, Avazeh, Anderson, Mark, Brooks, Claire, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Duncanson, Audrey, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas, Trynka, Gosia, Wijmenga, Cisca, Cazier, Jean-Baptiste, Atherfold, Paul, Nicholson, Anna M, Gellatly, Nichola L, Glancy, Deborah, Cooper, Sheldon C, Cunningham, David, Lind, Tore, Hapeshi, Julie, Ferry, David, Rathbone, Barrie, Brown, Julia, Love, Sharon, Attwood, Stephen, MacGregor, Stuart, Watson, Peter, Sanders, Scott, Ek, Weronica, Harrison, Rebecca F, Moayyedi, Paul, de Caestecker, John, Barr, Hugh, Stupka, Elia, Vaughan, Thomas L, Peltonen, Leena, Spencer, Chris C A, Tomlinson, Ian, Donnelly, Peter, and Jankowski, Janusz A Z

Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012
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47. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Author

Levine, David M, primary, Ek, Weronica E, additional, Zhang, Rui, additional, Liu, Xinxue, additional, Onstad, Lynn, additional, Sather, Cassandra, additional, Lao-Sirieix, Pierre, additional, Gammon, Marilie D, additional, Corley, Douglas A, additional, Shaheen, Nicholas J, additional, Bird, Nigel C, additional, Hardie, Laura J, additional, Murray, Liam J, additional, Reid, Brian J, additional, Chow, Wong-Ho, additional, Risch, Harvey A, additional, Nyrén, Olof, additional, Ye, Weimin, additional, Liu, Geoffrey, additional, Romero, Yvonne, additional, Bernstein, Leslie, additional, Wu, Anna H, additional, Casson, Alan G, additional, Chanock, Stephen J, additional, Harrington, Patricia, additional, Caldas, Isabel, additional, Debiram-Beecham, Irene, additional, Caldas, Carlos, additional, Hayward, Nicholas K, additional, Pharoah, Paul D, additional, Fitzgerald, Rebecca C, additional, MacGregor, Stuart, additional, Whiteman, David C, additional, and Vaughan, Thomas L, additional

Published
2013
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