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1. Dissecting the genetic heterogeneity of gastric cancer

Author

Hess, Timo, Maj, Carlo, Gehlen, Jan, Borisov, Oleg, Haas, Stephan L., Gockel, Ines, Vieth, Michael, Piessen, Guillaume, Alakus, Hakan, Vashist, Yogesh, Pereira, Carina, Knapp, Michael, Schüller, Vitalia, Quaas, Alexander, Grabsch, Heike I., Trautmann, Jessica, Malecka-Wojciesko, Ewa, Mokrowiecka, Anna, Speller, Jan, Mayr, Andreas, Schröder, Julia, Hillmer, Axel M., Heider, Dominik, Lordick, Florian, Pérez-Aísa, Ángeles, Campo, Rafael, Espinel, Jesús, Geijo, Fernando, Thomson, Concha, Bujanda, Luis, Sopeña, Federico, Lanas, Ángel, Pellisé, María, Pauligk, Claudia, Goetze, Thorsten Oliver, Zelck, Carolin, Reingruber, Julian, Hassanin, Emadeldin, Elbe, Peter, Alsabeah, Sandra, Lindblad, Mats, Nilsson, Magnus, Kreuser, Nicole, Thieme, René, Tavano, Francesca, Pastorino, Roberta, Arzani, Dario, Persiani, Roberto, Jung, Jin-On, Nienhüser, Henrik, Ott, Katja, Schumann, Ralf R., Kumpf, Oliver, Burock, Susen, Arndt, Volker, Jakubowska, Anna, Ławniczak, Małgorzta, Moreno, Victor, Martín, Vicente, Kogevinas, Manolis, Pollán, Marina, Dąbrowska, Justyna, Salas, Antonio, Cussenot, Olivier, Boland-Auge, Anne, Daian, Delphine, Deleuze, Jean-Francois, Salvi, Erika, Teder-Laving, Maris, Tomasello, Gianluca, Ratti, Margherita, Senti, Chiara, De Re, Valli, Steffan, Agostino, Hölscher, Arnulf H., Messerle, Katharina, Bruns, Christiane Josephine, Sīviņš, Armands, Bogdanova, Inga, Skieceviciene, Jurgita, Arstikyte, Justina, Moehler, Markus, Lang, Hauke, Grimminger, Peter P., Kruschewski, Martin, Vassos, Nikolaos, Schildberg, Claus, Lingohr, Philipp, Ridwelski, Karsten, Lippert, Hans, Fricker, Nadine, Krawitz, Peter, Hoffmann, Per, Nöthen, Markus M., Veits, Lothar, Izbicki, Jakob R., Mostowska, Adrianna, Martinón-Torres, Federico, Cusi, Daniele, Adolfsson, Rolf, Cancel-Tassin, Geraldine, Höblinger, Aksana, Rodermann, Ernst, Ludwig, Monika, Keller, Gisela, Metspalu, Andres, Brenner, Hermann, Heller, Joerg, Neef, Markus, Schepke, Michael, Dumoulin, Franz Ludwig, Hamann, Lutz, Cannizzaro, Renato, Ghidini, Michele, Plaßmann, Dominik, Geppert, Michael, Malfertheiner, Peter, Gehlen, Olivier, Skoczylas, Tomasz, Majewski, Marek, Lubiński, Jan, Palmieri, Orazio, Boccia, Stefania, Latiano, Anna, Aragones, Nuria, Schmidt, Thomas, Dinis-Ribeiro, Mário, Medeiros, Rui, Al-Batran, Salah-Eddin, Leja, Mārcis, Kupcinskas, Juozas, García-González, María A., Venerito, Marino, and Schumacher, Johannes

Published
2023
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2. Ösophagusdivertikel

Author

Gockel, Ines, primary, Kreuser, Nicole, additional, Brylla, Elke, additional, Bechmann, Ingo, additional, Trung, Kien Vu, additional, Hollenbach, Marcus, additional, Hoffmeister, Albrecht, additional, Dietz, Andreas, additional, and Wiegand, Susanne, additional

Published
2023
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3. Individualisierte Ösophaguschirurgie

Author

Mönig, Stefan P., Niclauss, Nadja, Zacherl, Johannes, Bonavina, Luigi, Bernardi, Daniele, Asti, Emanuele, Gockel, Ines, Kreuser, Nicole, Moulla, Yusef, Grimmiger, Peter, van Hillegersberg, Richard, Ruurda, J. P., van der Horst, S., van der Sluis, P. C., Korenkov, Michael, editor, Germer, Christoph-Thomas, editor, and Lang, Hauke, editor

Published
2021
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7. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study

Author

Dong, Jing, Gharahkhani, Puya, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Wu, Anna H., Ye, Weimin, Onstad, Lynn, Anderson, Lesley A., Bernstein, Leslie, Pharoah, Paul D., Risch, Harvey A., Corley, Douglas A., Fitzgerald, Rebecca C., Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Vaughan, Thomas L., MacGregor, Stuart, Love, Sharon, Palles, Claire, Tomlinson, Ian, Gockel, Ines, May, Andrea, Gerges, Christian, Anders, Mario, Böhmer, Anne C., Becker, Jessica, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Schmidt, Claudia, Izbicki, Jakob R., Hölscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M., Moebus, Susanne, Knapp, Michael, Peters, Wilbert H.M., Neuhaus, Horst, Rösch, Thomas, Ell, Christian, Jankowski, Janusz, Schumacher, Johannes, Neale, Rachel E., Whiteman, David C., and Thrift, Aaron P.

Published
2019
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9. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”

Author

Hess, Timo, primary, Maj, Carlo, additional, Gehlen, Jan, additional, Borisov, Oleg, additional, Haas, Stephan L., additional, Gockel, Ines, additional, Vieth, Michael, additional, Piessen, Guillaume, additional, Alakus, Hakan, additional, Vashist, Yogesh, additional, Pereira, Carina, additional, Knapp, Michael, additional, Schüller, Vitalia, additional, Quaas, Alexander, additional, Grabsch, Heike I., additional, Trautmann, Jessica, additional, Malecka-Wojciesko, Ewa, additional, Mokrowiecka, Anna, additional, Speller, Jan, additional, Mayr, Andreas, additional, Schröder, Julia, additional, Hillmer, Axel M., additional, Heider, Dominik, additional, Lordick, Florian, additional, Pérez-Aísa, Ángeles, additional, Campo, Rafael, additional, Espinel, Jesús, additional, Geijo, Fernando, additional, Thomson, Concha, additional, Bujanda, Luis, additional, Sopeña, Federico, additional, Lanas, Ángel, additional, Pellisé, María, additional, Pauligk, Claudia, additional, Goetze, Thorsten Oliver, additional, Zelck, Carolin, additional, Reingruber, Julian, additional, Hassanin, Emadeldin, additional, Elbe, Peter, additional, Alsabeah, Sandra, additional, Lindblad, Mats, additional, Nilsson, Magnus, additional, Kreuser, Nicole, additional, Thieme, René, additional, Tavano, Francesca, additional, Pastorino, Roberta, additional, Arzani, Dario, additional, Persiani, Roberto, additional, Jung, Jin-On, additional, Nienhüser, Henrik, additional, Ott, Katja, additional, Schumann, Ralf R., additional, Kumpf, Oliver, additional, Burock, Susen, additional, Arndt, Volker, additional, Jakubowska, Anna, additional, Ławniczak, Małgorzta, additional, Moreno, Victor, additional, Martín, Vicente, additional, Kogevinas, Manolis, additional, Pollán, Marina, additional, Dąbrowska, Justyna, additional, Salas, Antonio, additional, Cussenot, Olivier, additional, Boland-Auge, Anne, additional, Daian, Delphine, additional, Deleuze, Jean-Francois, additional, Salvi, Erika, additional, Teder-Laving, Maris, additional, Tomasello, Gianluca, additional, Ratti, Margherita, additional, Senti, Chiara, additional, De Re, Valli, additional, Steffan, Agostino, additional, Hölscher, Arnulf H., additional, Messerle, Katharina, additional, Bruns, Christiane Josephine, additional, Sīviņš, Armands, additional, Bogdanova, Inga, additional, Skieceviciene, Jurgita, additional, Arstikyte, Justina, additional, Moehler, Markus, additional, Lang, Hauke, additional, Grimminger, Peter P., additional, Kruschewski, Martin, additional, Vassos, Nikolaos, additional, Schildberg, Claus, additional, Lingohr, Philipp, additional, Ridwelski, Karsten, additional, Lippert, Hans, additional, Fricker, Nadine, additional, Krawitz, Peter, additional, Hoffmann, Per, additional, Nöthen, Markus M., additional, Veits, Lothar, additional, Izbicki, Jakob R., additional, Mostowska, Adrianna, additional, Martinón-Torres, Federico, additional, Cusi, Daniele, additional, Adolfsson, Rolf, additional, Cancel-Tassin, Geraldine, additional, Höblinger, Aksana, additional, Rodermann, Ernst, additional, Ludwig, Monika, additional, Keller, Gisela, additional, Metspalu, Andres, additional, Brenner, Hermann, additional, Heller, Joerg, additional, Neef, Markus, additional, Schepke, Michael, additional, Dumoulin, Franz Ludwig, additional, Hamann, Lutz, additional, Cannizzaro, Renato, additional, Ghidini, Michele, additional, Plaßmann, Dominik, additional, Geppert, Michael, additional, Malfertheiner, Peter, additional, Glehen, Olivier, additional, Skoczylas, Tomasz, additional, Majewski, Marek, additional, Lubiński, Jan, additional, Palmieri, Orazio, additional, Boccia, Stefania, additional, Latiano, Anna, additional, Aragones, Nuria, additional, Schmidt, Thomas, additional, Dinis-Ribeiro, Mário, additional, Medeiros, Rui, additional, Al-Batran, Salah-Eddin, additional, Leja, Mārcis, additional, Kupcinskas, Juozas, additional, García-González, María A., additional, Venerito, Marino, additional, and Schumacher, Johannes, additional

Published
2023
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11. 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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14. GWAS meta-analysis of 16 790 patients with Barrett’s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Author

Schröder, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan, Böhmer, Anne C., Borisov, Oleg, Hess, Timo, Kreuser, Nicole, Venerito, Marino, Alakus, Hakan, May, Andrea, Gerges, Christian, Schmidt, Thomas, Thieme, Rene, Heider, Dominik, Hillmer, Axel M., Reingruber, Julian, Lyros, Orestis, Dietrich, Arne, Hoffmeister, Albrecht, Mehdorn, Matthias, Lordick, Florian, Stocker, Gertraud, Hohaus, Michael, Reim, Daniel, Kandler, Jennis, Müller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J., Hölscher, Arnulf H., Lang, Hauke, Grimminger, Peter P., Dakkak, Dani, Vashist, Yogesh, May, Sandra, Görg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismüller, Josef, Dommermuth, Jens, Benner, Udo, Rösch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thaddäus T., Nöthen, Markus M., Dong, Jing, Ong, Jue-Sheng, Buas, Matthew F., Thrift, Aaron P., Vaughan, Thomas L., Tomlinson, Ian, Whiteman, David C., Fitzgerald, Rebecca Claire, Jankowski, Janusz, Vieth, Michael, Mayr, Andreas, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire, Schumacher, Johannes, Prenen, Hans, Wellcome Trust Case Control Consortium 2 (WTCCC2), Esophageal Adenocarcinoma Genetics Consortium (EAGLE), Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), Wellcome Trust Case Control Consortium 2 (WTCCC2), Esophageal Adenocarcinoma Genetics Consortium (EAGLE), and Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)

Subjects
Gastroenterology, Human medicine, Biology
Abstract

ObjectiveOesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.DesignWe combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.ResultsThe GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.ConclusionOur findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Published
2023

18. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author

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

Abstract

Background: Over 20 susceptibility single-nucleotide poly-morphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Published
2022

19. eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author

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

Published
2022
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21. Mismatch Repair Deficiency, Chemotherapy and Survival for Resectable Gastric Cancer: an Observational Study from the German staR Cohort and a Meta-Analysis

Author

Stolze, Thilo, primary, Franke, Sabine, additional, Haybaeck, Johannes, additional, Moehler, Markus, additional, Grimminger, Peter P., additional, Lang, Hauke, additional, Roth, Wilfried, additional, Gockel, Ines, additional, Kreuser, Nicole, additional, Bläker, Hendrik, additional, Wittekind, Christian, additional, Lordick, Florian, additional, Vieth, Michael, additional, Veits, Lothar, additional, Waidmann, Oliver, additional, Lingohr, Philipp, additional, Peitz, Ulrich, additional, Schildberg, Claus, additional, Kruschewski, Martin, additional, Vassos, Nikolaos, additional, Goni, Elisabetta, additional, Bruns, Christiane J., additional, Ridwelski, Karsten, additional, Wolff, Stefanie, additional, Lippert, Hans, additional, Schumacher, Johannes, additional, Malfertheiner, Peter, additional, and Venerito, Marino, additional

Published
2021
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22. Different Prevalence of Alarm, Dyspeptic and Reflux Symptoms in Patients with Cardia and Non-cardia Gastric Cancer

Author

Franck, Caspar, primary, Zimmermann, Nadja, primary, Goni, Elisabetta, primary, Lippert, Hans, primary, Ridwelski, Karsten, primary, Kruschewski, Martin, primary, Kreuser, Nicole, primary, Lingohr, Philipp, primary, Schildberg, Claus, primary, Vassos, Nikolaos, primary, Waidmann, Oliver, primary, Peitz, Ulrich, primary, Lang, Hauke, primary, Grmminger, Peter P, primary, Bruns, Christiane, primary, Veits, Lothar, primary, Vieth, Michael, primary, Moehler, Markus, primary, Lordick, Florian, primary, Gockel, Ines, primary, Schumacher, Johannes, primary, Malfertheiner, Peter, primary, and Venerito, Marino, primary

Published
2021
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23. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.

Abstract

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Published
2021

24. Different Prevalence of Alarm, Dyspeptic and Reflux Symptoms in Patients with Cardia and Non-cardia Gastric Cancer

Author

Franck, Caspar, Zimmermann, Nadja, Goni, Elisabetta, Lippert, Hans, Ridwelski, Karsten, Kruschewski, Martin, Kreuser, Nicole, Lingohr, Philipp, Schildberg, Claus, Vassos, Nikolaos, Waidmann, Oliver, Peitz, Ulrich, Lang, Hauke, Grmminger, Peter P., Bruns, Christiane, Veits, Lothar, Vieth, Michael, Moehler, Markus, Lordick, Florian, Gockel, Ines, Schumacher, Johannes, Malfertheiner, Peter, Venerito, Marino, Franck, Caspar, Zimmermann, Nadja, Goni, Elisabetta, Lippert, Hans, Ridwelski, Karsten, Kruschewski, Martin, Kreuser, Nicole, Lingohr, Philipp, Schildberg, Claus, Vassos, Nikolaos, Waidmann, Oliver, Peitz, Ulrich, Lang, Hauke, Grmminger, Peter P., Bruns, Christiane, Veits, Lothar, Vieth, Michael, Moehler, Markus, Lordick, Florian, Gockel, Ines, Schumacher, Johannes, Malfertheiner, Peter, and Venerito, Marino

Abstract

Background & Aims: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. Methods: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. Results: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p<0.0001), and were more likely to have Union for International Cancer Control (UICC) stage III-IV (54.1vs. 38.9%, p=0.0034). Especially, dysphagia and weight loss were more common in patients with cardia GC (49.2 vs. 6.4 %, p<0.0001 and 37.1 vs. 25.7%, p=0.02, respectively). No differences between the two groups were observed with respect to reflux symptoms. Patients with alarm symptoms were more likely to have UICC stage III-IV at presentation (69.4 vs. 42.9%, p<0.0001). Conclusions: In clinical practice the symptom pattern at presentation may serve as a hint for tumor localization. Despite the fact that they are common in the general population, dyspeptic symptoms offer a chance for earlier GC detection. Thus, in patients with dyspeptic symptoms who fail empiric approaches, endoscopy should not be delayed.

Published
2021

25. GWAS meta-analysis of 16 790 patients with Barrett’s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Author

Schro¨der, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan, Bo¨hmer, Anne C, Borisov, Oleg, Hess, Timo, Kreuser, Nicole, Venerito, Marino, Alakus, Hakan, May, Andrea, Gerges, Christian, Schmidt, Thomas, Thieme, Rene, Heider, Dominik, Hillmer, Axel M, Reingruber, Julian, Lyros, Orestis, Dietrich, Arne, Hoffmeister, Albrecht, Mehdorn, Matthias, Lordick, Florian, Stocker, Gertraud, Hohaus, Michael, Reim, Daniel, Kandler, Jennis, Mu¨ller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J, Ho¨lscher, Arnulf H, Lang, Hauke, Grimminger, Peter P, Dakkak, Dani, Vashist, Yogesh, May, Sandra, Go¨rg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismu¨ller, Josef, Dommermuth, Jens, Benner, Udo, Ro¨sch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thadda¨us T, No¨then, Markus M, Dong, Jing, Ong, Jue-Sheng, Buas, Matthew F, Thrift, Aaron P, Vaughan, Thomas L, Tomlinson, Ian, Whiteman, David C, Fitzgerald, Rebecca Claire, Jankowski, Janusz, Vieth, Michael, Mayr, Andreas, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire, and Schumacher, Johannes

Abstract

ObjectiveOesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.DesignWe combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.ResultsThe GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.ConclusionOur findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Published
2023
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26. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Author

Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, Schumacher, Johannes, Boehmer, Anne C., Hecker, Julian, Schroeder, Julia, Gharahkhani, Puya, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dietrich, Arne, Moulla, Yusef, Lyros, Orestis, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Meismueller, Josef, Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Noethen, Markus M., Whiteman, David C., Tomlinson, Ian, Jankowski, Janusz, Fitzgerald, Rebecca C., Palles, Claire, Vaughan, Thomas L., Gockel, Ines, Thrift, Aaron P., Fier, Heide, and Schumacher, Johannes

Abstract

Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association metaanalyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (r(g) = 0.13, P = 2 x 10(-04)) and a r(g) of 0.12 between WHR and BE/EA (P = 1 x 10(-02)). Sexspecific analyses revealed a pronounced genetic correlation between BMI and EA in females (r(g) = 0.17, P = 1.2 x 10(-03)), and WHR and EA in males (r(g) = 0.18, P = 1.51 x 10(-02)). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 x 10(-03)) and WHR and BE/EA risk variants (P = 2 x 10(-02)). Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mechanisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

Published
2020

27. Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research

Author

Weise, Friederike, Vieth, Michael, Reinhold, Dirk, Haybaeck, Johannes, Goni, Elisabetta, Lippert, Hans, Ridwelski, Karsten, Lingohr, Philipp, Schildberg, Claus, Vassos, Nikolaos, Kruschewski, Martin, Krasniuk, Iurii, Grimminger, Peter P., Waidmann, Oliver, Peitz, Ulrich, Veits, Lothar, Kreuser, Nicole, Lang, Hauke, Bruns, Christiane, Moehler, Markus, Lordick, Florian, Gockel, Ines, Schumacher, Johannes, Malfertheiner, Peter, Venerito, Marino, Weise, Friederike, Vieth, Michael, Reinhold, Dirk, Haybaeck, Johannes, Goni, Elisabetta, Lippert, Hans, Ridwelski, Karsten, Lingohr, Philipp, Schildberg, Claus, Vassos, Nikolaos, Kruschewski, Martin, Krasniuk, Iurii, Grimminger, Peter P., Waidmann, Oliver, Peitz, Ulrich, Veits, Lothar, Kreuser, Nicole, Lang, Hauke, Bruns, Christiane, Moehler, Markus, Lordick, Florian, Gockel, Ines, Schumacher, Johannes, Malfertheiner, Peter, and Venerito, Marino

Abstract

Objectives Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study. Methods Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire. Results Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 +/- 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0-7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6-187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2-116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3-28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0-9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8-85.6) and 53.5% (50.9-56.1), respectively (OR 0.25, 95% CI 0.08-0.75, p = 0.001). Conclusions Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.

Published
2020

28. Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma

Author

Dighe, Shruti G, primary, Chen, Jianhong, additional, Yan, Li, additional, He, Qianchuan, additional, Gharahkhani, Puya, additional, Onstad, Lynn, additional, Levine, David M, additional, Palles, Claire, additional, Ye, Weimin, additional, Gammon, Marilie D, additional, Iyer, Prasad G, additional, Anderson, Lesley A, additional, Liu, Geoffrey, additional, Wu, Anna H, additional, Dai, James Y, additional, Chow, Wong-Ho, additional, Risch, Harvey A, additional, Lagergren, Jesper, additional, Shaheen, Nicholas J, additional, Bernstein, Leslie, additional, Corley, Douglas A, additional, Prenen, Hans, additional, deCaestecker, John, additional, MacDonald, David, additional, Moayyedi, Paul, additional, Barr, Hugh, additional, Love, Sharon B, additional, Chegwidden, Laura, additional, Attwood, Stephen, additional, Watson, Peter, additional, Harrison, Rebecca, additional, Ott, Katja, additional, Moebus, Susanne, additional, Venerito, Marino, additional, Lang, Hauke, additional, Mayershofer, Rupert, additional, Knapp, Michael, additional, Veits, Lothar, additional, Gerges, Christian, additional, Weismüller, Josef, additional, Gockel, Ines, additional, Vashist, Yogesh, additional, Nöthen, Markus M, additional, Izbicki, Jakob R, additional, Manner, Hendrik, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Böhmer, Anne C, additional, Hölscher, Arnulf H, additional, Anders, Mario, additional, Pech, Oliver, additional, Schumacher, Brigitte, additional, Schmidt, Claudia, additional, Schmidt, Thomas, additional, Noder, Tania, additional, Lorenz, Dietmar, additional, Vieth, Michael, additional, May, Andrea, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Becker, Jessica, additional, Ell, Christian, additional, Ambrosone, Christine B, additional, Moysich, Kirsten B, additional, MacGregor, Stuart, additional, Tomlinson, Ian, additional, Whiteman, David C, additional, Jankowski, Janusz, additional, Schumacher, Johannes, additional, Vaughan, Thomas L, additional, Madeleine, Margaret M, additional, Hardie, Laura J, additional, and Buas, Matthew F, additional

Published
2020
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31. Gastric cancer in autoimmune gastritis: A case‐control study from the German centers of the staR project on gastric cancer research

Author

Weise, Friederike, primary, Vieth, Michael, additional, Reinhold, Dirk, additional, Haybaeck, Johannes, additional, Goni, Elisabetta, additional, Lippert, Hans, additional, Ridwelski, Karsten, additional, Lingohr, Philipp, additional, Schildberg, Claus, additional, Vassos, Nikolaos, additional, Kruschewski, Martin, additional, Krasniuk, Iurii, additional, Grimminger, Peter P, additional, Waidmann, Oliver, additional, Peitz, Ulrich, additional, Veits, Lothar, additional, Kreuser, Nicole, additional, Lang, Hauke, additional, Bruns, Christiane, additional, Moehler, Markus, additional, Lordick, Florian, additional, Gockel, Ines, additional, Schumacher, Johannes, additional, Malfertheiner, Peter, additional, and Venerito, Marino, additional

Published
2020
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32. Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Author

Böhmer, Anne C., primary, Hecker, Julian, additional, Schröder, Julia, additional, Gharahkhani, Puya, additional, May, Andrea, additional, Gerges, Christian, additional, Anders, Mario, additional, Becker, Jessica, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Thieme, René, additional, Noder, Tania, additional, Venerito, Marino, additional, Veits, Lothar, additional, Schmidt, Thomas, additional, Fuchs, Claudia, additional, Izbicki, Jakob R., additional, Hölscher, Arnulf H., additional, Dietrich, Arne, additional, Moulla, Yusef, additional, Lyros, Orestis, additional, Lang, Hauke, additional, Lorenz, Dietmar, additional, Schumacher, Brigitte, additional, Mayershofer, Rupert, additional, Vashist, Yogesh, additional, Ott, Katja, additional, Vieth, Michael, additional, Weismüller, Josef, additional, Moebus, Susanne, additional, Knapp, Michael, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Ell, Christian, additional, Nöthen, Markus M., additional, Whiteman, David C., additional, Tomlinson, Ian, additional, Jankowski, Janusz, additional, Fitzgerald, Rebecca C., additional, Palles, Claire, additional, Vaughan, Thomas L., additional, Gockel, Ines, additional, Thrift, Aaron P., additional, Fier, Heide, additional, and Schumacher, Johannes, additional

Published
2020
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33. Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Author

Schroeder, Julia, Schueller, Vitalia, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Ludwig, Kerstin U., Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dakkak, Dani, Jansen-Winkeln, Boris, Moulla, Yusef, Lyros, Orestis, Niebisch, Stefan, Mehdorn, Matthias, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Mangold, Elisabeth, Noethen, Markus M., Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, Schumacher, Johannes, Boehmer, Anne C., Schroeder, Julia, Schueller, Vitalia, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Hess, Timo, Kreuser, Nicole, Thieme, Rene, Ludwig, Kerstin U., Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Fuchs, Claudia, Izbicki, Jakob R., Hoelscher, Arnulf H., Dakkak, Dani, Jansen-Winkeln, Boris, Moulla, Yusef, Lyros, Orestis, Niebisch, Stefan, Mehdorn, Matthias, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Mangold, Elisabeth, Noethen, Markus M., Moebus, Susanne, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, Schumacher, Johannes, and Boehmer, Anne C.

Abstract

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta -analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5x10(-8)) and novel candidate loci (5x10(-8) <= P <= 5x10(-5)). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, P-combined = 3.16x10(-7) and rs1540, P-combined = 4.16x10(-6)) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in

Published
2019

34. Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Author

Schröder, Julia, primary, Schüller, Vitalia, additional, May, Andrea, additional, Gerges, Christian, additional, Anders, Mario, additional, Becker, Jessica, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Thieme, René, additional, Ludwig, Kerstin U., additional, Noder, Tania, additional, Venerito, Marino, additional, Veits, Lothar, additional, Schmidt, Thomas, additional, Fuchs, Claudia, additional, Izbicki, Jakob R., additional, Hölscher, Arnulf H., additional, Dakkak, Dani, additional, Jansen-Winkeln, Boris, additional, Moulla, Yusef, additional, Lyros, Orestis, additional, Niebisch, Stefan, additional, Mehdorn, Matthias, additional, Lang, Hauke, additional, Lorenz, Dietmar, additional, Schumacher, Brigitte, additional, Mayershofer, Rupert, additional, Vashist, Yogesh, additional, Ott, Katja, additional, Vieth, Michael, additional, Weismüller, Josef, additional, Mangold, Elisabeth, additional, Nöthen, Markus M., additional, Moebus, Susanne, additional, Knapp, Michael, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Ell, Christian, additional, Gockel, Ines, additional, Schumacher, Johannes, additional, and Böhmer, Anne C., additional

Published
2019
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35. Ablative Therapieoptionen beim lokal fortgeschrittenen, irresektablen und grenzwertig resektablen Pankreaskarzinom

Author

Moulla, Yusef, primary, Petersen, Tim-Ole, additional, Maiwald, Bettina, additional, Bailis, Nikolaos, additional, Kreuser, Nicole, additional, Lordick, Florian, additional, Seehofer, Daniel, additional, Sucher, Robert, additional, Hecker, Martin, additional, Hoffmeister, Albrecht, additional, Jansen-Winkeln, Boris, additional, and Gockel, Ines, additional

Published
2019
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36. First genotype‐phenotype study reveals HLA‐DQβ1 insertion heterogeneity in high‐resolution manometry achalasia subtypes

Author

Vackova, Zuzana, primary, Niebisch, Stefan, additional, Triantafyllou, Tania, additional, Becker, Jessica, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Kanoni, Stavroula, additional, Deloukas, Panos, additional, Schüller, Vitalia, additional, Heinrichs, Sophie KM, additional, Thieme, René, additional, Nöthen, Markus M, additional, Knapp, Michael, additional, Spicak, Julius, additional, Gockel, Ines, additional, Schumacher, Johannes, additional, Theodorou, Dimitris, additional, and Martinek, Jan, additional

Published
2019
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38. Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Author

Heinrichs, Sophie K. M., Hess, Timo, Becker, Jessica, Hamann, Lutz, Vashist, Yogesh K., Butterbach, Katja, Schmidt, Thomas, Alakus, Hakan, Krasniuk, Iurii, Hoeblinger, Aksana, Lingohr, Philipp, Ludwig, Monika, Hagel, Alexander F., Schildberg, Claus W., Veits, Lothar, Gyvyte, Ugne, Weise, Katharina, Schueller, Vitalia, Boehmer, Anne C., Schroeder, Julia, Gehlen, Jan, Kreuser, Nicole, Hofer, Sebastian, Lang, Hauke, Lordick, Florian, Malfertheiner, Peter, Moehler, Markus, Pech, Oliver, Vassos, Nikolaos, Rodermann, Ernst, Izbicki, Jakob R., Kruschewski, Martin, Ott, Katja, Schumann, Ralf R., Vieth, Michael, Mangold, Elisabeth, Gasenko, Evita, Kupcinskas, Limas, Brenner, Hermann, Grimminger, Peter, Bujanda, Luis, Sopena, Federico, Espinel, Jesus, Thomson, Concha, Perez-Aisa, Angeles, Campo, Rafael, Geijo, Fernando, Collette, Daniela, Bruns, Christiane, Messerle, Katharina, Gockel, Ines, Noethen, Markus M., Lippert, Hans, Ridwelski, Karsten, Lanas, Angel, Keller, Gisela, Knapp, Michael, Leja, Marcis, Kupcinskas, Juozas, Garcia-Gonzalez, Maria A., Venerito, Marino, Schumacher, Johannes, Heinrichs, Sophie K. M., Hess, Timo, Becker, Jessica, Hamann, Lutz, Vashist, Yogesh K., Butterbach, Katja, Schmidt, Thomas, Alakus, Hakan, Krasniuk, Iurii, Hoeblinger, Aksana, Lingohr, Philipp, Ludwig, Monika, Hagel, Alexander F., Schildberg, Claus W., Veits, Lothar, Gyvyte, Ugne, Weise, Katharina, Schueller, Vitalia, Boehmer, Anne C., Schroeder, Julia, Gehlen, Jan, Kreuser, Nicole, Hofer, Sebastian, Lang, Hauke, Lordick, Florian, Malfertheiner, Peter, Moehler, Markus, Pech, Oliver, Vassos, Nikolaos, Rodermann, Ernst, Izbicki, Jakob R., Kruschewski, Martin, Ott, Katja, Schumann, Ralf R., Vieth, Michael, Mangold, Elisabeth, Gasenko, Evita, Kupcinskas, Limas, Brenner, Hermann, Grimminger, Peter, Bujanda, Luis, Sopena, Federico, Espinel, Jesus, Thomson, Concha, Perez-Aisa, Angeles, Campo, Rafael, Geijo, Fernando, Collette, Daniela, Bruns, Christiane, Messerle, Katharina, Gockel, Ines, Noethen, Markus M., Lippert, Hans, Ridwelski, Karsten, Lanas, Angel, Keller, Gisela, Knapp, Michael, Leja, Marcis, Kupcinskas, Juozas, Garcia-Gonzalez, Maria A., Venerito, Marino, and Schumacher, Johannes

Abstract

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

Published
2018

39. Evidence for PTGER4 ,PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Author

Heinrichs, Sophie K. M., primary, Hess, Timo, additional, Becker, Jessica, additional, Hamann, Lutz, additional, Vashist, Yogesh K., additional, Butterbach, Katja, additional, Schmidt, Thomas, additional, Alakus, Hakan, additional, Krasniuk, Iurii, additional, Höblinger, Aksana, additional, Lingohr, Philipp, additional, Ludwig, Monika, additional, Hagel, Alexander F., additional, Schildberg, Claus W., additional, Veits, Lothar, additional, Gyvyte, Ugne, additional, Weise, Katharina, additional, Schüller, Vitalia, additional, Böhmer, Anne C., additional, Schröder, Julia, additional, Gehlen, Jan, additional, Kreuser, Nicole, additional, Hofer, Sebastian, additional, Lang, Hauke, additional, Lordick, Florian, additional, Malfertheiner, Peter, additional, Moehler, Markus, additional, Pech, Oliver, additional, Vassos, Nikolaos, additional, Rodermann, Ernst, additional, Izbicki, Jakob R., additional, Kruschewski, Martin, additional, Ott, Katja, additional, Schumann, Ralf R., additional, Vieth, Michael, additional, Mangold, Elisabeth, additional, Gasenko, Evita, additional, Kupcinskas, Limas, additional, Brenner, Hermann, additional, Grimminger, Peter, additional, Bujanda, Luis, additional, Sopeña, Federico, additional, Espinel, Jesús, additional, Thomson, Concha, additional, Pérez-Aísa, Ángeles, additional, Campo, Rafael, additional, Geijo, Fernando, additional, Collette, Daniela, additional, Bruns, Christiane, additional, Messerle, Katharina, additional, Gockel, Ines, additional, Nöthen, Markus M., additional, Lippert, Hans, additional, Ridwelski, Karsten, additional, Lanas, Angel, additional, Keller, Gisela, additional, Knapp, Michael, additional, Leja, Marcis, additional, Kupcinskas, Juozas, additional, García-González, Maria A., additional, Venerito, Marino, additional, and Schumacher, Johannes, additional

Published
2018
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40. Stress biomarkers in minimally invasive and conventional colorectal resections

Author

Netto, Jeffrey, primary, Jansen-Winkeln, Boris, additional, Thieme, René, additional, Eckardt, Jan, additional, Ju Bae, Yoon, additional, Willenberg, Anja, additional, Huppert, Sabine, additional, Lyros, Orestes, additional, Niebisch, Stefan, additional, Allecke, Friederike, additional, Kreuser, Nicole, additional, Kratzsch, Jürgen, additional, Kaiser, Thorsten, additional, Ceglarek, Uta, additional, Thiery, Joachim, additional, and Gockel, Ines, additional

Published
2018
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41. 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

42. First Genotype-Phenotype Study in Achalasia Implies that the HLA-DQB1-Insertion Affects Different High-Resolution Manometry (HRM) Manifestation of the Disease

Author

Vackova, Zuzana, primary, Niebisch, Stefan, additional, Triantafilou, Tania, additional, Becker, Jessica, additional, Kosiol, Nils, additional, Kreuser, Nicole, additional, Schüller, Vitalia, additional, Heinrichs, Sophie, additional, Hess, Timo, additional, Nöthen, Markus, additional, Knapp, Michael, additional, Spicak, Julius, additional, Gockel, Ines, additional, Schumacher, Johannes, additional, Theodorou, Dimitris, additional, and Martinek, Jan, additional

Published
2017
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44. The Barrett-associated variants at GDF7 and TBX5 also increase esophageal adenocarcinoma risk

Author

Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Schmidt, Claudia, Veits, Lothar, Noder, Tania, Mayershofer, Rupert, Kreuser, Nicole, Manner, Hendrik, Venerito, Marino, Hofer, Jan-Hinnerk, Lyros, Orestis, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Heinrichs, Sophie K. M., Weise, Katharina, Hess, Timo, Boehmer, Anne C., Kosiol, Nils, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Ott, Katja, Schmidt, Thomas, Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, Schumacher, Johannes, Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Schmidt, Claudia, Veits, Lothar, Noder, Tania, Mayershofer, Rupert, Kreuser, Nicole, Manner, Hendrik, Venerito, Marino, Hofer, Jan-Hinnerk, Lyros, Orestis, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Heinrichs, Sophie K. M., Weise, Katharina, Hess, Timo, Boehmer, Anne C., Kosiol, Nils, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Ott, Katja, Schmidt, Thomas, Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Knapp, Michael, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, and Schumacher, Johannes

Abstract

Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) represent two stages within the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence. Previously genetic risk factors have been identified that confer risk to BE and EAC development. However, to which extent the genetic variants confer risk to different stages of the BE/EAC sequence remains mainly unknown. In this study we analyzed three most recently identified BE variants at the genes GDF7 (rs3072), TBX5 (rs2701108), and ALDH1A2 (rs3784262) separately in BE and EAC samples in order to determine their risk effects during BE/EAC sequence. Our data show that rs3072 at GDF7 and rs2701108 at TBX5 are also associated with EAC and conclude that both loci confer disease risk also at later stages of the BE/EAC sequence. In contrast, rs3784262 at ALDH1A2 was highly significantly associated with BE, but showed no association with EAC. Our data do not provide evidence that the ALDH1A2 locus confers equal risk in early and late stages of BE/EAC sequence.

Published
2016

45. 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

46. Comprehensive epidemiological and genotype–phenotype analyses in a large European sample with idiopathic achalasia

Author

Becker, Jessica, primary, Niebisch, Stefan, additional, Ricchiuto, Arcangelo, additional, Schaich, Eva J., additional, Lehmann, Gavin, additional, Waltgenbach, Tobias, additional, Schafft, Annette, additional, Hess, Timo, additional, Lenze, Frank, additional, Venerito, Marino, additional, Hüneburg, Robert, additional, Lingohr, Philipp, additional, Matthaei, Hanno, additional, Seewald, Stefan, additional, Scheuermann, Uwe, additional, Kreuser, Nicole, additional, Veits, Lothar, additional, Wouters, Mira M., additional, Gockel, Henning R., additional, Lang, Hauke, additional, Vieth, Michael, additional, Müller, Michaela, additional, Eckardt, Alexander J., additional, von Rahden, Burkhard H.A., additional, Knapp, Michael, additional, Boeckxstaens, Guy E., additional, Fimmers, Rolf, additional, Nöthen, Markus M., additional, Schulz, Henning G., additional, Gockel, Ines, additional, and Schumacher, Johannes, additional

Published
2016
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47. 241 Association of the HLA-DQB1-insertion in Idiopathic Achalasia and First Genotype-Phenotype (GxP) Study Using High-Resolution Manometry Data

Author

Vackova, Zuzana, primary, Niebisch, Stefan, additional, Becker, Jessica, additional, Kosiol, Nils, additional, Kreuser, Nicole, additional, Schüller, Vitalia, additional, Heinrichs, Sophie, additional, Hess, Timo, additional, Nöthen, Markus M., additional, Gockel, Ines, additional, Spicak, Julius, additional, Schumacher, Johannes, additional, and Martinek, Jan, additional

Published
2016
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48. The Barrett‐associated variants atGDF 7andTBX 5also increase esophageal adenocarcinoma risk

Author

Becker, Jessica, primary, May, Andrea, additional, Gerges, Christian, additional, Anders, Mario, additional, Schmidt, Claudia, additional, Veits, Lothar, additional, Noder, Tania, additional, Mayershofer, Rupert, additional, Kreuser, Nicole, additional, Manner, Hendrik, additional, Venerito, Marino, additional, Hofer, Jan‐Hinnerk, additional, Lyros, Orestis, additional, Ahlbrand, Constantin J., additional, Arras, Michael, additional, Hofer, Sebastian, additional, Heinrichs, Sophie K. M., additional, Weise, Katharina, additional, Hess, Timo, additional, Böhmer, Anne C., additional, Kosiol, Nils, additional, Kiesslich, Ralf, additional, Izbicki, Jakob R., additional, Hölscher, Arnulf H., additional, Bollschweiler, Elfriede, additional, Malfertheiner, Peter, additional, Lang, Hauke, additional, Moehler, Markus, additional, Lorenz, Dietmar, additional, Ott, Katja, additional, Schmidt, Thomas, additional, Nöthen, Markus M., additional, Hackelsberger, Andreas, additional, Schumacher, Brigitte, additional, Pech, Oliver, additional, Vashist, Yogesh, additional, Vieth, Michael, additional, Weismüller, Josef, additional, Knapp, Michael, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Ell, Christian, additional, Gockel, Ines, additional, and Schumacher, Johannes, additional

Published
2016
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50. GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Author

Schroeder, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan, Boehmer, Anne C., Borisov, Oleg, Hess, Timo, Kreuser, Nicole, Venerito, Marino, Alakus, Hakan, May, Andrea, Gerges, Christian, Schmidt, Thomas, Thieme, Rene, Heider, Dominik, Hillmer, Axel M., Reingruber, Julian, Lyros, Orestis, Dietrich, Arne, Hoffmeister, Albrecht, Mehdorn, Matthias, Lordick, Florian, Stocker, Gertraud, Hohaus, Michael, Reim, Daniel, Kandler, Jennis, Mueller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J., Holscher, Arnulf H., Lang, Hauke, Grimminger, Peter P., Dakkak, Dani, Vashist, Yogesh, May, Sandra, Gorg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismuller, Josef, Dommermuth, Jens, Benner, Udo, Roesch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thaddaus T., Noethen, Markus M., Dong, Jing, Ong, Jue-Sheng, Buas, Matthew F., Thrift, Aaron P., Vaughan, Thomas L., Tomlinson, Ian, Whiteman, David C., Fitzgerald, Rebecca Claire, Jankowski, Janusz, Vieth, Michael, Mayr, Andreas, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire, Schumacher, Johannes, Schroeder, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan, Boehmer, Anne C., Borisov, Oleg, Hess, Timo, Kreuser, Nicole, Venerito, Marino, Alakus, Hakan, May, Andrea, Gerges, Christian, Schmidt, Thomas, Thieme, Rene, Heider, Dominik, Hillmer, Axel M., Reingruber, Julian, Lyros, Orestis, Dietrich, Arne, Hoffmeister, Albrecht, Mehdorn, Matthias, Lordick, Florian, Stocker, Gertraud, Hohaus, Michael, Reim, Daniel, Kandler, Jennis, Mueller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J., Holscher, Arnulf H., Lang, Hauke, Grimminger, Peter P., Dakkak, Dani, Vashist, Yogesh, May, Sandra, Gorg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismuller, Josef, Dommermuth, Jens, Benner, Udo, Roesch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thaddaus T., Noethen, Markus M., Dong, Jing, Ong, Jue-Sheng, Buas, Matthew F., Thrift, Aaron P., Vaughan, Thomas L., Tomlinson, Ian, Whiteman, David C., Fitzgerald, Rebecca Claire, Jankowski, Janusz, Vieth, Michael, Mayr, Andreas, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire, and Schumacher, Johannes

Abstract

Objective Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. Design We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. Results The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. Conclusion Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

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