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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. 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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4. 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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5. 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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6. 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

7. 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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8. The engagement of selectins and their ligands in colorectal cancer liver metastases

Author: Paschos, Konstantinos A., Canovas, David, and Bird, Nigel C.
Published: 2010
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9. 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., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, 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., Whiteman, David C., MacGregor, Stuart, other, and, An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, 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., Whiteman, David C., MacGregor, Stuart, and other, and
Abstract: 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

10. 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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11. 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, Esophageal Cancer Consortium, 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, and Wu, Anna H.
Subjects: CANCER susceptibility, VITAMIN D, BASAL cell carcinoma, OVARIAN cancer
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. Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers. [ABSTRACT FROM AUTHOR]
Published: 2021
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12. 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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13. 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

14. 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

15. 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, Barrett's And Esophageal Adenocarcinoma Consortium (BEACON), Esophageal Adenocarcinoma GenEtics Consortium (EAGLE), Wellcome Trust Case Control Consortium 2 (WTCCC2), Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, De Caestecker, 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 HM, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Fitzgerald, Rebecca [0000-0002-3434-3568], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Risk, Barrett Esophagus, Esophageal Neoplasms, Humans, Adenocarcinoma, Polymorphism, Single Nucleotide, digestive system diseases, Genome-Wide Association Study
Abstract: BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p
Published: 2016

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

Author: Li, Wenguang, primary, Bird, Nigel C., additional, and Luo, Xiaoyu, additional
Published: 2017
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18. 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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19. 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

20. 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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21. 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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22. 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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23. 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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24. 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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25. 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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26. 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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27. 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

28. 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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29. 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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30. 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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31. 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

32. 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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33. The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

Author: Van den Eynden, Gert G., primary, Majeed, Ali W., additional, Illemann, Martin, additional, Vermeulen, Peter B., additional, Bird, Nigel C., additional, Høyer-Hansen, Gunilla, additional, Eefsen, Rikke Løvendahl, additional, Reynolds, Andrew R., additional, and Brodt, Pnina, additional
Published: 2013
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34. The engagement of selectins and their ligands in colorectal cancer liver metastases

Author: Paschos, Konstantinos A., primary, Canovas, David, additional, and Bird, Nigel C., additional
Published: 2009
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35. The NAD(P)H:quinone oxidoreductase I C609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma

Author: di Martino, Erica, primary, Hardie, Laura J, additional, Wild, Christopher P, additional, Gong, Yun Y, additional, Olliver, Joanna R, additional, Gough, Martin D, additional, and Bird, Nigel C, additional
Published: 2007
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36. A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus.

Author: Dai, James Y., de Dieu Tapsoba, Jean, Buas, Matthew F., Onstad, Lynn E., Levine, David M., Risch, Harvey A., Wong-Ho Chow, Bernstein, Leslie, Weimin Ye, Lagergren, Jesper, Bird, Nigel C., Corley, Douglas A., Shaheen, Nicholas J., Wu, Anna H., Reid, Brian J., Hardie, Laura J., Whiteman, David C., and Vaughan, Thomas L.
Abstract: Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear. Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma. Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index. Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1. Impact: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]
Published: 2015
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37. Early increases in plasminogen activator activity following partial hepatectomy in humans

Author: Mangnall, David, Smith, Kirsty, Bird, Nigel C, and Majeed, Ali W
Subjects: Research
Abstract: BACKGROUND: Increases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. Remodelling of the extracellular matrix, conversion of single chain hepatocyte growth factor to the active two-chain form and a possible activation of a mitogenic signalling pathway have all been ascribed to the increased uPA activity. The present study aimed to determine whether similar early increases in uPA activity could be detected in the remnant liver following resection of metastatic tumours in surgical patients. RESULTS: Eighteen patients undergoing partial hepatectomy for the removal of hepatic metastases secondary to primary colonic tumours were studied. Increased plasminogen activator activity was found in the final liver samples for the group of patients in whom the resection size was at least 50%. For smaller resections, the increased activity was not observed. The increased activity did not correlate with the age of the patient or with the time between the start of resection and the end of the operation. There was, however, a negative correlation between plasminogen activator activity and the time for which blood supply to the liver was clamped. CONCLUSIONS: Our findings are in accordance with those from experimental animal models and show, for the first time, that rapid increases in plasminogen activator activity can occur following similarly large liver resection in humans. Thus, increases in plasminogen activator activity are an early event in the remnant liver following major liver resection in man. Our observations provide support for the contention that increases in plasminogen activators play a key role in the initiation of hepatic regeneration in man.
Published: 2004

38. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk.

Author: Eunjung Lee, Stram, Daniel O., Ek, Weronica E., Onstad, Lynn E., MacGregor, Stuart, Gharahkhani, Puya, Weimin Ye, Lagergren, Jesper, Shaheen, Nicholas J., Murray, Liam J., Hardie, Laura J., Gammon, Marilie D., Wong-Ho Chow, Risch, Harvey A., Corley, Douglas A., Levine, David M., Whiteman, David C., Bernstein, Leslie, Bird, Nigel C., and Vaughan, Thomas L.
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 ofEAand Barrett's esophagus. [ABSTRACT FROM AUTHOR]
Published: 2015
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39. Effects of Pro-Inflammatory Cytokines on the Production of Soluble Fractalkine and ADAM17 by HepG2 Cells.

Author: Turner, Sharon L., Mangnall, David, Bird, Nigel C., Blair-Zajdel, Maria E., and Bunning, Rowena A. D.
Subjects: *LIVER cancer patients, *CYTOKINES, *ENZYME-linked immunosorbent assay, *LIVER cells, *FLOW cytometry, *TUMOR necrosis factors, *REVERSE transcriptase polymerase chain reaction, *GENE transfection
Abstract: Background & Aims: Soluble fractalkine is increased in the liver during times of injury; however the effect of pro-inflammatory cytokines in this process is currently unknown. The aim of this study was to determine whether pro-inflammatory cytokines elevated in patients with hepatocellular carcinoma influence fractalkine shedding from HepG2 cells and whether ADAM17 was involved in this process. Methods: In vitro experiments were performed in the human hepatocellular carcinoma cell line HepG2. Soluble fractalkine was detected using an ELISA. ADAM17 expression was investigated using quantitative real time (reverse transcription)-polymerase chain reaction and flow cytometry. Short interfering RNA transfection was used to down-regulate ADAM17 expression. Results: Soluble fractalkine was present in supernatants of HepG2 cells, and was significantly increased by interleukin-1β (p⩽0.005) and tumour necrosis factor-α (p⩽0.043), but not by interleukin- 6 (p⩾0.316). This corresponded to minor increases in ADAM17 protein, but not ADAM17 mRNA, following the same treatments. However, the down-regulation of ADAM17 protein did not affect fractalkine shedding. Conclusions: This study showed that soluble fractalkine is up-regulated under inflammatory conditions associated with hepatocellular carcinoma development, but ADAM17 does not appear to be responsible for regulating this process. [ABSTRACT FROM AUTHOR]
Published: 2010

40. The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications.

Author: den Eynden, Gert G. Van, Majeed, Ali W., Illemann, Martin, Vermeulen, Peter B., Bird, Nigel C., Høyer-Hansen, Gunilla, Eefsen, Rikke Løvendahl, Reynolds, Andrew R., and Brodt, Pnina
Subjects: *METASTASIS, *COLON cancer, *RECTAL cancer, *LIVER cancer, *CHEMOKINES
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. [ABSTRACT FROM AUTHOR]
Published: 2013
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41. Tumor stromal phenotypes define VEGF sensitivity--letter.

Author: Van den Eynden GG, Bird NC, Dirix LY, Eefsen RL, Gao ZH, Høyer-Hansen G, Illemann M, Majeed AW, Metrakos P, Reynolds AR, Vainer B, van Dam PJ, Van Laere SJ, Vermeulen PB, Vidal-Vanaclocha F, and Brodt P
Subjects: Humans, Antibodies, Monoclonal, Humanized administration & dosage, Neoplasms genetics, Stromal Cells metabolism, Vascular Endothelial Growth Factor A genetics
Published: 2014
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42. Natural history of hepatic metastases from colorectal cancer--pathobiological pathways with clinical significance.

Author: Paschos KA, Majeed AW, and Bird NC
Subjects: Apoptosis, Cadherins metabolism, Cell Adhesion Molecules metabolism, Hepatic Stellate Cells cytology, Humans, Kupffer Cells pathology, Liver pathology, Matrix Metalloproteinases metabolism, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Treatment Outcome, Colorectal Neoplasms pathology, Liver Neoplasms secondary
Abstract: Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.
Published: 2014
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43. Liver regeneration and its impact on post-hepatectomy metastatic tumour recurrence.

Author: Paschos KA and Bird NC
Subjects: Hepatocyte Growth Factor physiology, Humans, Neoplasm Recurrence, Local, Transforming Growth Factor beta1 physiology, Tumor Necrosis Factor-alpha physiology, Hepatectomy, Liver Neoplasms secondary, Liver Neoplasms surgery, Liver Regeneration
Abstract: Hepatic resection remains the primary potentially curative therapeutic modality for liver metastases. The regenerative process that occurs postoperatively is a complex phenomenon, orchestrated by molecular cascades involving growth factors, cytokines, proteolytic enzymes and other proteins. Unfortunately, some of these molecules, such as hepatocyte growth factor, tumour growth factor beta and matrix metalloproteinases also promote tumour growth and may contribute to the recurrence of liver metastasis. The reactivation of dormant micrometastases or the intrahepatic accumulation of circulating malignant cells has been suggested as the responsible mechanism, although not clearly understood. Current clinical and experimental research has developed inhibitors of several regenerative molecules, attempting to treat tumour reappearance within the liver. Despite the considerable progress of the last decade, multiple queries remain to be clarified concerning liver regeneration, as well as its impact on post-hepatectomy tumour recurrence. This review describes the responsible molecular pathways and the clinical importance of post-hepatectomy liver regeneration, and investigates how the regenerative process may promote metastatic tumour recurrence.
Published: 2010

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