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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, Schumacher, Johannes, 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
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

2. 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, Schumacher, Johannes, 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
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

3. 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, Schumacher, Johannes, 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
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
Full Text: View/download PDF

4. 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, Schumacher, Johannes, 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
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
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5. 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, Schumacher, Johannes, 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
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me, Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709
Published: 2023
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6. Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

Author: Scheiner, Bernhard, Roessler, Daniel, Phen, Samuel, Lim, Mir, Pomej, Katharina, Pressiani, Tiziana, Cammarota, Antonella, Fründt, Thorben W, von Felden, Johann, Schulze, Kornelius, Himmelsbach, Vera, Finkelmeier, Fabian, Deibel, Ansgar; https://orcid.org/0000-0001-6208-9694, Siebenhüner, Alexander R; https://orcid.org/0000-0002-5404-2383, Shmanko, Kateryna, Radu, Pompilia, Schwacha-Eipper, Birgit, Ebert, Matthias P, Teufel, Andreas, Djanani, Angela, Hucke, Florian, Balcar, Lorenz; https://orcid.org/0000-0002-6708-3061, Philipp, Alexander B, Hsiehchen, David, Venerito, Marino, Sinner, Friedrich, Trauner, Michael, D'Alessio, Antonio, Fulgenzi, Claudia A M, Pinato, David J, et al, Scheiner, Bernhard, Roessler, Daniel, Phen, Samuel, Lim, Mir, Pomej, Katharina, Pressiani, Tiziana, Cammarota, Antonella, Fründt, Thorben W, von Felden, Johann, Schulze, Kornelius, Himmelsbach, Vera, Finkelmeier, Fabian, Deibel, Ansgar; https://orcid.org/0000-0001-6208-9694, Siebenhüner, Alexander R; https://orcid.org/0000-0002-5404-2383, Shmanko, Kateryna, Radu, Pompilia, Schwacha-Eipper, Birgit, Ebert, Matthias P, Teufel, Andreas, Djanani, Angela, Hucke, Florian, Balcar, Lorenz; https://orcid.org/0000-0002-6708-3061, Philipp, Alexander B, Hsiehchen, David, Venerito, Marino, Sinner, Friedrich, Trauner, Michael, D'Alessio, Antonio, Fulgenzi, Claudia A M, Pinato, David J, and et al
Abstract: BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreat
Published: 2023

7. 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

8. Atezolizumab Plus Bevacizumab in Patients with Advanced and Progressing Hepatocellular Carcinoma: Retrospective Multicenter Experience

Author: Sinner, Friedrich, Pinter, Matthias, Scheiner, Bernhard, Ettrich, Thomas Jens, Sturm, Niklas, Gonzalez-Carmona, Maria A., Waidmann, Oliver, Finkelmeier, Fabian, Himmelsbach, Vera, De Toni, Enrico N., Ben Khaled, Najib, Mohr, Raphael, Fruendt, Thorben Wilhelm, Kuetting, Fabian, van Boemmel, Florian, Lieb, Sabine, Krug, Sebastian, Bettinger, Dominik, Schultheiss, Michael, Jochheim, Leonie S., Best, Jan, Mueller, Christian, Keitel, Verena, Venerito, Marino, Sinner, Friedrich, Pinter, Matthias, Scheiner, Bernhard, Ettrich, Thomas Jens, Sturm, Niklas, Gonzalez-Carmona, Maria A., Waidmann, Oliver, Finkelmeier, Fabian, Himmelsbach, Vera, De Toni, Enrico N., Ben Khaled, Najib, Mohr, Raphael, Fruendt, Thorben Wilhelm, Kuetting, Fabian, van Boemmel, Florian, Lieb, Sabine, Krug, Sebastian, Bettinger, Dominik, Schultheiss, Michael, Jochheim, Leonie S., Best, Jan, Mueller, Christian, Keitel, Verena, and Venerito, Marino
Abstract: Simple Summary Hepatocellular cancer is the most common type of primary liver cancer. It is the third leading cause of cancer-related deaths worldwide and its incidence is increasing: >1 million new cases per year expected by 2025. Despite advances in treatment in recent years, diagnosis is associated with poor overall survival. Treatment of hepatocellular cancer depends on the patient's general health and fitness, how well the liver is working, the number and size of tumors in the liver, and whether or not the tumor has spread to other neighboring or distant parts of the body. The combination of atezolizumab plus bevacizumab, two intravenously administered antibodies, is the preferred first-line treatment for patients with advanced hepatocellular cancer that has spread from the liver to other neighboring or distant parts of the body. This study investigated how long patients whose hepatocellular cancer continues to grow (progress) despite one or more prior tumor therapies live when they receive atezolizumab plus bevacizumab. These patients, treated with atezolizumab plus bevacizumab at various hospitals in Germany and Austria, lived about 16 months, which is about 5-8 months longer than patients receiving approved drugs. The safety profile was consistent with previous reports. Atezolizumab plus bevacizumab is the standard of care for first-line systemic therapy for advanced hepatocellular carcinoma (aHCC). Data on the efficacy and safety of atezolizumab plus bevacizumab in patients with aHCC who have received prior systemic therapy are not available. Methods: Patients with aHCC who received atezolizumab plus bevacizumab after at least one systemic treatment between December 2018 and March 2022 were retrospectively identified in 13 centers in Germany and Austria. Patient characteristics, tumor response rates, progression-free survival (PFS), overall survival (OS), and adverse events (AE) were analyzed. Results: A total of 50 patients were identified; 41 (82%) were m
Published: 2022

9. Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol

Author: Ben Khaled, Najib, Seidensticker, Max, Ricke, Jens, Mayerle, Julia, Oehrle, Bettina, Roessler, Daniel, Teupser, Daniel, Ehmer, Ursula, Bitzer, Michael, Waldschmidt, Dirk, Fuchs, Martin, Reuken, Philipp A., Lange, Christian M., Wege, Henning, Kandulski, Arne, Dechene, Alexander, Venerito, Marino, Berres, Marie-Luise, Luedde, Tom, Kubisch, Ilja, Reiter, Florian P., De Toni, Enrico N., Ben Khaled, Najib, Seidensticker, Max, Ricke, Jens, Mayerle, Julia, Oehrle, Bettina, Roessler, Daniel, Teupser, Daniel, Ehmer, Ursula, Bitzer, Michael, Waldschmidt, Dirk, Fuchs, Martin, Reuken, Philipp A., Lange, Christian M., Wege, Henning, Kandulski, Arne, Dechene, Alexander, Venerito, Marino, Berres, Marie-Luise, Luedde, Tom, Kubisch, Ilja, Reiter, Florian P., and De Toni, Enrico N.
Abstract: The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase 2 study is the first trial to evaluate the safety and efficacy of atezolizumab bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life.
Published: 2022

10. Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg)

Author: Burgos-Santamaría, Diego, Nyssen, Olga P, Gasbarrini, Antonio, Vaira, Dino, Pérez-Aisa, Ángele, Rodrigo, Luí, Pellicano, Rinaldo, Keco-Huerga, Alma, Pabón-Carrasco, Manuel, Castro-Fernandez, Manuel, Boltin, Doron, Barrio, Jesu, Phull, Perminder, Kupcinskas, Juoza, Jonaitis, Laima, Ortiz-Polo, Inmaculada, Tepes, Bojan, Lucendo, Alfredo J, Huguet, José María, Areia, Miguel, Jurecic, Natasa Brglez, Denkovski, Maja, Bujanda, Luí, Ramos-San Román, June, Cuadrado-Lavín, Antonio, Gomez-Camarero, Judith, Jiménez Moreno, Manuel Alfonso, Lanas, Angel, Martinez-Dominguez, Samuel Jesú, Alfaro, Enrique, Marcos-Pinto, Ricardo, Milivojevic, Vladimir, Rokkas, Theodore, Leja, Marci, Smith, Sinead, Tonkić, Ante, Buzás, György Mikló, Doulberis, Michael, Venerito, Marino, Lerang, Frode, Bordin, Dmitry S, Lamy, Vincent, Capelle, Lisette G, Marlicz, Wojciech, Dobru, Daniela, Gridnyev, Oleksiy, Puig, Ignasi, Mégraud, Franci, O'Morain, Colm, Gisbert, Javier P, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Burgos-Santamaría, Diego, Nyssen, Olga P, Gasbarrini, Antonio, Vaira, Dino, Pérez-Aisa, Ángele, Rodrigo, Luí, Pellicano, Rinaldo, Keco-Huerga, Alma, Pabón-Carrasco, Manuel, Castro-Fernandez, Manuel, Boltin, Doron, Barrio, Jesu, Phull, Perminder, Kupcinskas, Juoza, Jonaitis, Laima, Ortiz-Polo, Inmaculada, Tepes, Bojan, Lucendo, Alfredo J, Huguet, José María, Areia, Miguel, Jurecic, Natasa Brglez, Denkovski, Maja, Bujanda, Luí, Ramos-San Román, June, Cuadrado-Lavín, Antonio, Gomez-Camarero, Judith, Jiménez Moreno, Manuel Alfonso, Lanas, Angel, Martinez-Dominguez, Samuel Jesú, Alfaro, Enrique, Marcos-Pinto, Ricardo, Milivojevic, Vladimir, Rokkas, Theodore, Leja, Marci, Smith, Sinead, Tonkić, Ante, Buzás, György Mikló, Doulberis, Michael, Venerito, Marino, Lerang, Frode, Bordin, Dmitry S, Lamy, Vincent, Capelle, Lisette G, Marlicz, Wojciech, Dobru, Daniela, Gridnyev, Oleksiy, Puig, Ignasi, Mégraud, Franci, O'Morain, Colm, Gisbert, Javier P, and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)
Abstract: Objective To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe. Design International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociacion Espanola de Gastroenterologia-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis. Results Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed > 90% of cases. Overall effectiveness remained < 90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p < 0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted & GE;14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%. Conclusion Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update.
Published: 2022

11. Empirical Second-Line Therapy in 5000 Patients of the European Registry on Helicobacter pylori Management (Hp-EuReg)

Author: Nyssen, Olga P., Vaira, Dino, Pérez Aísa, Ángeles, Rodrigo, Luis, Castro-Fernandez, Manuel, Jonaitis, Laimas, Tepes, Bojan, Vologzhanina, Liudmila, Caldas, María, Lanas, Angel, Lucendo, Alfredo J., Bujanda, Luis, Ortuño, Juan, Barrio, Jesús, Huguet, Jose M., Voynovan, Irina, Lasala, Jorge Perez, Sarsenbaeva, Aiman Silkanovna, Fernandez-Salazar, Luis, Molina-Infante, Javier, Jurecic, Natasa Brglez, Areia, Miguel, Gasbarrini, Antonio, Kupčinskas, Juozas, Bordin, Dmitry, Marcos-Pinto, Ricardo, Lerang, Frode, Leja, Marcis, Buzas, Gyorgy M., Niv, Yaron, Rokkas, Theodore, Phull, Perminder, Smith, Sinead, Shvets, Oleg, Venerito, Marino, Milivojevic, Vladimir, Simsek, Ilkay, Lamy, Vincent, Bytzer, Peter, Boyanova, Lyudmila, Kunovský, Lumír, Beglinger, Christoph, Doulberis, Michael, Marlicz, Wojciech, Goldis, Adrian, Tonkić, Ante, Capelle, Lisette, Puig, Ignasi, Megraud, Francis, Morain, Colm O’, Nyssen, Olga P., Vaira, Dino, Pérez Aísa, Ángeles, Rodrigo, Luis, Castro-Fernandez, Manuel, Jonaitis, Laimas, Tepes, Bojan, Vologzhanina, Liudmila, Caldas, María, Lanas, Angel, Lucendo, Alfredo J., Bujanda, Luis, Ortuño, Juan, Barrio, Jesús, Huguet, Jose M., Voynovan, Irina, Lasala, Jorge Perez, Sarsenbaeva, Aiman Silkanovna, Fernandez-Salazar, Luis, Molina-Infante, Javier, Jurecic, Natasa Brglez, Areia, Miguel, Gasbarrini, Antonio, Kupčinskas, Juozas, Bordin, Dmitry, Marcos-Pinto, Ricardo, Lerang, Frode, Leja, Marcis, Buzas, Gyorgy M., Niv, Yaron, Rokkas, Theodore, Phull, Perminder, Smith, Sinead, Shvets, Oleg, Venerito, Marino, Milivojevic, Vladimir, Simsek, Ilkay, Lamy, Vincent, Bytzer, Peter, Boyanova, Lyudmila, Kunovský, Lumír, Beglinger, Christoph, Doulberis, Michael, Marlicz, Wojciech, Goldis, Adrian, Tonkić, Ante, Capelle, Lisette, Puig, Ignasi, Megraud, Francis, and Morain, Colm O’
Abstract: Background & Aims: After a first Helicobacter pylori eradication attempt, approximately 20% of patients will remain infected. The aim of the current study was to assess the effectiveness and safety of second-line empiric treatment in Europe. Methods: This international, multicenter, prospective, non-interventional registry aimed to evaluate the decisions and outcomes of H pylori management by European gastroenterologists. All infected adult cases with a previous eradication treatment attempt were registered with the Spanish Association of Gastroenterology–Research Electronic Data Capture until February 2021. Patients allergic to penicillin and those who received susceptibility-guided therapy were excluded. Data monitoring was performed to ensure data quality. Results: Overall, 5055 patients received empiric second-line treatment. Triple therapy with amoxicillin and levofloxacin was prescribed most commonly (33%). The overall effectiveness was 82% by modified intention-to-treat analysis and 83% in the per-protocol population. After failure of first-line clarithromycin-containing treatment, optimal eradication (>90%) was obtained with moxifloxacin-containing triple therapy or levofloxacin-containing quadruple therapy (with bismuth). In patients receiving triple therapy containing levofloxacin or moxifloxacin, and levofloxacin–bismuth quadruple treatment, cure rates were optimized with 14-day regimens using high doses of proton pump inhibitors. However, 3-in-1 single capsule or levofloxacin–bismuth quadruple therapy produced reliable eradication rates regardless of proton pump inhibitor dose, duration of therapy, or previous first-line treatment. The overall incidence of adverse events was 28%, and most (85%) were mild. Three patients developed serious adverse events (0.3%) requiring hospitalization. Conclusions: Empiric second-line regimens including 14-day quinolone triple therapies, 14-day levofloxacin–bismuth quadruple therapy, 14-day tetracycline–bismuth
Published: 2022

12. Efficacy and safety of atezolizumab and bevacizumab in the real-world treatment of advanced hepatocellular carcinoma: Experience from four tertiary centers

Author: Himmelsbach, Vera, Pinter, Matthias, Scheiner, Bernhard, Venerito, Marino, Sinner, Friedrich, Zimpel, Carolin, Marquardt, Jens, Trojan, Jörg, Waidmann, Oliver, Finkelmeier, Fabian, Himmelsbach, Vera, Pinter, Matthias, Scheiner, Bernhard, Venerito, Marino, Sinner, Friedrich, Zimpel, Carolin, Marquardt, Jens, Trojan, Jörg, Waidmann, Oliver, and Finkelmeier, Fabian
Abstract: The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data on the safety and efficacy of A + B in real life. We included patients with advanced HCC treated with A + B as first-line therapy at four cancer centers in Germany and Austria between December 2018 and August 2021. Demographics, overall survival (OS), and adverse events were assessed until 15 September 2021. We included 66 patients. Most patients had compensated cirrhosis (n = 34; 52%), while Child–Pugh class B cirrhosis was observed in 23 patients (35%), and class C cirrhosis in 5 patients (8%). The best responses included a complete response (CR) in 7 patients (11%), a partial response (PR) in 12 patients (18%), stable disease (SD) in 22 patients (33%), and progressive disease in 11 patients (17%). The median progression-free (PFS) survival was 6.5 months, while the median overall survival (OS) was not reached in this cohort (6-month OS: 69%, 12-month OS: 60%, 18-month OS: 58%). Patients with viral hepatitis seemed to have a better prognosis than patients with HCC of non-viral etiology. The real-world PFS and OS were comparable to those of the pivotal IMBRAVE trial, despite including patients with worse liver function in this study. We conclude that A + B is also highly effective in a real-life setting, with manageable toxicity, especially in patients with compensated liver disease. In patients with compromised liver function (Child B and C), the treatment showed low efficacy and, therefore, it should be well considered before administration to these patients.
Published: 2022

13. 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

14. 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

15. Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort

Author: Finkelmeier, Fabian, Scheiner, Bernhard, Leyh, Catherine, Best, Jan, Fruendt, Thorben Wilhelm, Czauderna, Carolin, Beutel, Alica, Bettinger, Dominik, WeiSS, Johannes, Meischl, Tobias, Kuetting, Fabian, Waldschmidt, Dirk-Thomas, Radu, Pompilia, Schultheiss, Michael, Peiffer, Kai-Henrik, Ettrich, Thomas J., Weinmann, Arndt, Wege, Henning, Venerito, Marino, Dufour, Jean-Francois, Lange, Christian M., Pinter, Matthias, Waidmann, Oliver, Finkelmeier, Fabian, Scheiner, Bernhard, Leyh, Catherine, Best, Jan, Fruendt, Thorben Wilhelm, Czauderna, Carolin, Beutel, Alica, Bettinger, Dominik, WeiSS, Johannes, Meischl, Tobias, Kuetting, Fabian, Waldschmidt, Dirk-Thomas, Radu, Pompilia, Schultheiss, Michael, Peiffer, Kai-Henrik, Ettrich, Thomas J., Weinmann, Arndt, Wege, Henning, Venerito, Marino, Dufour, Jean-Francois, Lange, Christian M., Pinter, Matthias, and Waidmann, Oliver
Abstract: Background and Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients' characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease - in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to
Published: 2021

16. 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

17. Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort

Author: Finkelmeier, Fabian, Scheiner, Bernhard, Leyh, Catherine, Best, Jan, Fruendt, Thorben Wilhelm, Czauderna, Carolin, Beutel, Alica, Bettinger, Dominik, WeiSS, Johannes, Meischl, Tobias, Kuetting, Fabian, Waldschmidt, Dirk-Thomas, Radu, Pompilia, Schultheiss, Michael, Peiffer, Kai-Henrik, Ettrich, Thomas J., Weinmann, Arndt, Wege, Henning, Venerito, Marino, Dufour, Jean-Francois, Lange, Christian M., Pinter, Matthias, Waidmann, Oliver, Finkelmeier, Fabian, Scheiner, Bernhard, Leyh, Catherine, Best, Jan, Fruendt, Thorben Wilhelm, Czauderna, Carolin, Beutel, Alica, Bettinger, Dominik, WeiSS, Johannes, Meischl, Tobias, Kuetting, Fabian, Waldschmidt, Dirk-Thomas, Radu, Pompilia, Schultheiss, Michael, Peiffer, Kai-Henrik, Ettrich, Thomas J., Weinmann, Arndt, Wege, Henning, Venerito, Marino, Dufour, Jean-Francois, Lange, Christian M., Pinter, Matthias, and Waidmann, Oliver
Abstract: Background and Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients' characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease - in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to
Published: 2021

18. 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

19. Comparative efficacy of cabozantinib and ramucirumab after sorafenib for patients with hepatocellular carcinoma and alpha-fetoprotein ≥ 400 ng/ml : a matching-adjusted indirect comparison

Author: Trojan, Jörg, Mollon, Patrick, Daniele, Bruno, Marteau, Florence, Martín, Lidia, Li, Yuxin, Xu, Qing, Piscaglia, Fabio, Zaucha, Renata, Sarker, Debashis, Lim, Ho Yeong, Venerito, Marino, Trojan, Jörg, Mollon, Patrick, Daniele, Bruno, Marteau, Florence, Martín, Lidia, Li, Yuxin, Xu, Qing, Piscaglia, Fabio, Zaucha, Renata, Sarker, Debashis, Lim, Ho Yeong, and Venerito, Marino
Abstract: Individual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.
Published: 2021

20. European Registry on Helicobacter pylori management (Hp-EuReg):Patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients

Author: Nyssen, Olga P., Bordin, Dmitry, Tepes, Bojan, Pérez-Aisa, Ángeles, Vaira, Dino, Caldas, Maria, Bujanda, Luis, Castro-Fernandez, Manuel, Lerang, Frode, Leja, Marcis, Rodrigo, Luís, Rokkas, Theodore, Kupcinskas, Limas, Pérez-Lasala, Jorge, Jonaitis, Laimas, Shvets, Oleg, Gasbarrini, Antonio, Simsek, Halis, Axon, Anthony T.R., Buzás, György, Machado, Jose Carlos, Niv, Yaron, Boyanova, Lyudmila, Goldis, Adrian, Lamy, Vincent, Tonkic, Ante, Przytulski, Krzysztof, Beglinger, Christoph, Venerito, Marino, Bytzer, Peter, Capelle, Lisette, Milosavljević, Tomica, Milivojevic, Vladimir, Veijola, Lea, Molina-Infante, Javier, Vologzhanina, Liudmila, Fadeenko, Galina, Ariño, Ines, Fiorini, Giulia, Garre, Ana, Garrido, Jesús, F Pérez, Cristina, Puig, Ignasi, Heluwaert, Frederic, Megraud, Francis, O'Morain, Colm, Gisbert, Javier P., Nyssen, Olga P., Bordin, Dmitry, Tepes, Bojan, Pérez-Aisa, Ángeles, Vaira, Dino, Caldas, Maria, Bujanda, Luis, Castro-Fernandez, Manuel, Lerang, Frode, Leja, Marcis, Rodrigo, Luís, Rokkas, Theodore, Kupcinskas, Limas, Pérez-Lasala, Jorge, Jonaitis, Laimas, Shvets, Oleg, Gasbarrini, Antonio, Simsek, Halis, Axon, Anthony T.R., Buzás, György, Machado, Jose Carlos, Niv, Yaron, Boyanova, Lyudmila, Goldis, Adrian, Lamy, Vincent, Tonkic, Ante, Przytulski, Krzysztof, Beglinger, Christoph, Venerito, Marino, Bytzer, Peter, Capelle, Lisette, Milosavljević, Tomica, Milivojevic, Vladimir, Veijola, Lea, Molina-Infante, Javier, Vologzhanina, Liudmila, Fadeenko, Galina, Ariño, Ines, Fiorini, Giulia, Garre, Ana, Garrido, Jesús, F Pérez, Cristina, Puig, Ignasi, Heluwaert, Frederic, Megraud, Francis, O'Morain, Colm, and Gisbert, Javier P.
Abstract: Objective The best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care. Design International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylori management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed. Results 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pylori treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%). Conclusion Management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.
Published: 2021

21. 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

22. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author: Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, Thrift, Aaron P., Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/ EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
Published: 2020

23. 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

24. 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

25. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author: Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, Thrift, Aaron P., Dong, Jing, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes, and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/ EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
Published: 2020

26. 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

27. Helicobacter pylori first-line and rescue treatments in patients allergic to penicillin:Experience from the European Registry on H pylori management (Hp-EuReg)

Author: Nyssen, Olga P., Pérez-Aisa, Ángeles, Tepes, Bojan, Rodrigo-Sáez, Luis, Romero, Pilar M., Lucendo, Alfredo, Castro-Fernández, Manuel, Phull, Perminder, Barrio, Jesús, Bujanda, Luis, Ortuño, Juan, Areia, Miguel, Brglez Jurecic, Natasa, Huguet, José María, Alcaide, Noelia, Voynovan, Irina, María Botargues Bote, José, Modolell, Inés, Pérez Lasala, Jorge, Ariño, Inés, Jonaitis, Laimas, Dominguez-Cajal, Manuel, Buzas, György, Lerang, Frode, Perona, Monica, Bordin, Dmitry, Axon, Toni, Gasbarrini, Antonio, Marcos Pinto, Ricardo, Niv, Yaron, Kupcinskas, Limas, Tonkic, Ante, Leja, Marcis, Rokkas, Theodore, Boyanova, Lyudmila, Shvets, Oleg, Venerito, Marino, Bytzer, Peter, Goldis, Adrian, Simsek, Ilkay, Lamy, Vincent, Przytulski, Krzysztof, Kunovský, Lumír, Capelle, Lisette, Milosavljevic, Tomica, Caldas, María, Garre, Ana, Mégraud, Francis, O'Morain, Colm, Gisbert, Javier P., Nyssen, Olga P., Pérez-Aisa, Ángeles, Tepes, Bojan, Rodrigo-Sáez, Luis, Romero, Pilar M., Lucendo, Alfredo, Castro-Fernández, Manuel, Phull, Perminder, Barrio, Jesús, Bujanda, Luis, Ortuño, Juan, Areia, Miguel, Brglez Jurecic, Natasa, Huguet, José María, Alcaide, Noelia, Voynovan, Irina, María Botargues Bote, José, Modolell, Inés, Pérez Lasala, Jorge, Ariño, Inés, Jonaitis, Laimas, Dominguez-Cajal, Manuel, Buzas, György, Lerang, Frode, Perona, Monica, Bordin, Dmitry, Axon, Toni, Gasbarrini, Antonio, Marcos Pinto, Ricardo, Niv, Yaron, Kupcinskas, Limas, Tonkic, Ante, Leja, Marcis, Rokkas, Theodore, Boyanova, Lyudmila, Shvets, Oleg, Venerito, Marino, Bytzer, Peter, Goldis, Adrian, Simsek, Ilkay, Lamy, Vincent, Przytulski, Krzysztof, Kunovský, Lumír, Capelle, Lisette, Milosavljevic, Tomica, Caldas, María, Garre, Ana, Mégraud, Francis, O'Morain, Colm, and Gisbert, Javier P.
Abstract: Background: Experience in Helicobacter pylori eradication treatment of patients allergic to penicillin is very scarce. A triple combination with a PPI, clarithromycin (C), and metronidazole (M) is often prescribed as the first option, although more recently the use of a quadruple therapy with PPI, bismuth (B), tetracycline (T), and M has been recommended. Aim: To evaluate the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin in the “European Registry of H pylori management” (Hp-EuReg). Methods: A systematic prospective registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H pylori infection. An e-CRF was created on AEG-REDCap. Patients with penicillin allergy were analyzed until June 2019. Results: One-thousand eighty-four patients allergic to penicillin were analyzed. The most frequently prescribed first-line treatments were as follows: PPI + C + M (n = 285) and PPI + B + T + M (classic or Pylera®; n = 250). In first line, the efficacy of PPI + C + M was 69%, while PPI + B + T + M reached 91% (P <.001). In second line, after the failure of PPI + C + M, two rescue options showed similar efficacy: PPI + B + T + M (78%) and PPI + C + levofloxacin (L) (71%) (P >.05). In third line, after the failure of PPI + C + M and PPI + C + L, PPI + B + T + M was successful in 75% of cases. Conclusion: In patients allergic to penicillin, a triple combination with PPI + C + M should not be generally recommended as a first-line treatment, while a quadruple regimen with PPI + B + T + M seems to be a better option. As a rescue treatment, this quadruple regimen (if not previously prescribed) or a triple regimen with PPI + C + L could be used but achieved suboptimal (<80%) results.
Published: 2020

28. 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, Bohmer, Anne C., Becker, Jessica, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Schmidt, Claudia, Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Nothen, Markus M., Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, Jankowski, Janusz, Schumacher, Johannes, Neale, Rachel E., Whiteman, David C., Thrift, Aaron P., 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, Bohmer, Anne C., Becker, Jessica, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Schmidt, Claudia, Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Nothen, Markus M., Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, Jankowski, Janusz, Schumacher, Johannes, Neale, Rachel E., Whiteman, David C., and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH) D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.
Published: 2019

29. 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

30. 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, Bohmer, Anne C., Becker, Jessica, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Schmidt, Claudia, Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Nothen, Markus M., Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, Jankowski, Janusz, Schumacher, Johannes, Neale, Rachel E., Whiteman, David C., Thrift, Aaron P., 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, Bohmer, Anne C., Becker, Jessica, Kreuser, Nicole, Thieme, Rene, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Schmidt, Claudia, Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Mayershofer, Rupert, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Nothen, Markus M., Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, Jankowski, Janusz, Schumacher, Johannes, Neale, Rachel E., Whiteman, David C., and Thrift, Aaron P.
Abstract: BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH) D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.
Published: 2019

31. 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

32. Helicobacter Pylori Eradication Therapy is Not Associated with the Onset of Inflammatory Bowel Diseases. A Case-Control Study

Author: Rosania, Rosa, Von Arnim, Ulrike, Link, Alexander, Rajilić-Stojanović, Mirjana, Franck, Caspar, Canbay, Ali, Malfertheiner, Peter, Venerito, Marino, Rosania, Rosa, Von Arnim, Ulrike, Link, Alexander, Rajilić-Stojanović, Mirjana, Franck, Caspar, Canbay, Ali, Malfertheiner, Peter, and Venerito, Marino
Abstract: Background & Aims: A negative association between H. pylori and inflammatory bowel disease (IBD) has been previously reported. There were also case reports suggesting a new onset of IBD 6-12 months after H. pylori eradication therapy. In a case-control study we investigated whether previous H. pylori eradication therapy was associated with the risk of developing IBD. Methods: IBD outpatients with both Crohn's disease (CD) and ulcerative colitis (UC) were enrolled. Age- and sex-matched blood donors served as controls in a 1:2 fashion. Information on demographics, medical history, previous H. pylori infection and eradication therapy was recorded. Serum samples for H. pylori serology testing (anti-H. pylori-IgG and anti-CagA-IgG) were obtained. Controls that received H. pylori eradication therapy during the 12 months previous to enrollment were excluded. Results: Overall, 127 IBD patients (CD N= 90; UC N= 37) and 254 controls were enrolled. The prevalence of H. pylori infection (positive H. pylori serology and/or previous eradication) in IBD patients and controls was 11% and 23%, respectively (OR 0.4, 95% CI 0.21-0.74, p lt 0.003). Four patients (3%) developed IBD (3 MC and 1 CU) after receiving successful H. pylori eradication (latency 6-12 months). The rate of previous H. pylori eradication therapy in patents who successively developed IBD was lower but not statistically different from that observed in the control group (OR 0.43, 95% CI 0.14-1.29, p=0.16). Conclusions: In our study previous H. pylori eradication therapy was not associated with the onset of IBD. Whether in a subgroup of patients, H. pylori eradication therapy may trigger a latent IBD, cannot be excluded.
Published: 2018

33. 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

34. 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

35. Helicobacter Pylori Eradication Therapy is Not Associated with the Onset of Inflammatory Bowel Diseases. A Case-Control Study

Author: Rosania, Rosa, Von Arnim, Ulrike, Link, Alexander, Rajilić-Stojanović, Mirjana, Franck, Caspar, Canbay, Ali, Malfertheiner, Peter, Venerito, Marino, Rosania, Rosa, Von Arnim, Ulrike, Link, Alexander, Rajilić-Stojanović, Mirjana, Franck, Caspar, Canbay, Ali, Malfertheiner, Peter, and Venerito, Marino
Abstract: Background & Aims: A negative association between H. pylori and inflammatory bowel disease (IBD) has been previously reported. There were also case reports suggesting a new onset of IBD 6-12 months after H. pylori eradication therapy. In a case-control study we investigated whether previous H. pylori eradication therapy was associated with the risk of developing IBD. Methods: IBD outpatients with both Crohn's disease (CD) and ulcerative colitis (UC) were enrolled. Age- and sex-matched blood donors served as controls in a 1:2 fashion. Information on demographics, medical history, previous H. pylori infection and eradication therapy was recorded. Serum samples for H. pylori serology testing (anti-H. pylori-IgG and anti-CagA-IgG) were obtained. Controls that received H. pylori eradication therapy during the 12 months previous to enrollment were excluded. Results: Overall, 127 IBD patients (CD N= 90; UC N= 37) and 254 controls were enrolled. The prevalence of H. pylori infection (positive H. pylori serology and/or previous eradication) in IBD patients and controls was 11% and 23%, respectively (OR 0.4, 95% CI 0.21-0.74, p lt 0.003). Four patients (3%) developed IBD (3 MC and 1 CU) after receiving successful H. pylori eradication (latency 6-12 months). The rate of previous H. pylori eradication therapy in patents who successively developed IBD was lower but not statistically different from that observed in the control group (OR 0.43, 95% CI 0.14-1.29, p=0.16). Conclusions: In our study previous H. pylori eradication therapy was not associated with the onset of IBD. Whether in a subgroup of patients, H. pylori eradication therapy may trigger a latent IBD, cannot be excluded.
Published: 2018

36. 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

37. 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

38. 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, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, 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, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, 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, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, 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, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
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< 5 x 10(-8)). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p= 4 .8 x 10(-1)), MSRA (rs17749155; p= 5.2 x 10(-1) x)
Published: 2016

39. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

40. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

41. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

42. 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

43. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

44. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

45. 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

46. 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, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, 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, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, 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, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, 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, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes
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< 5 x 10(-8)). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p= 4 .8 x 10(-1)), MSRA (rs17749155; p= 5.2 x 10(-1) x)
Published: 2016

47. 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

48. 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, Schumacher, Johannes, 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
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<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC0020
Published: 2016

49. Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma

Author: Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Veits, Lothar, Weise, Katharina, Czamara, Darina, Lyros, Orestis, Manner, Hendrik, Terheggen, Grischa, Venerito, Marino, Noder, Tania, Mayershofer, Rupert, Hofer, Jan-Hinnerk, Karch, Hans-Werner, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Heinrichs, Sophie K. M., Hess, Timo, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Mueller-Myhsok, Bertram, Ott, Katja, Schmidt, Thomas, Whiteman, David C., Vaughan, Thomas L., Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, Schumacher, Johannes, Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Veits, Lothar, Weise, Katharina, Czamara, Darina, Lyros, Orestis, Manner, Hendrik, Terheggen, Grischa, Venerito, Marino, Noder, Tania, Mayershofer, Rupert, Hofer, Jan-Hinnerk, Karch, Hans-Werner, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Heinrichs, Sophie K. M., Hess, Timo, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Mueller-Myhsok, Bertram, Ott, Katja, Schmidt, Thomas, Whiteman, David C., Vaughan, Thomas L., Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, and Schumacher, Johannes
Abstract: The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P< 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P<10(-5)) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.
Published: 2015

50. Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma

Author: Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Veits, Lothar, Weise, Katharina, Czamara, Darina, Lyros, Orestis, Manner, Hendrik, Terheggen, Grischa, Venerito, Marino, Noder, Tania, Mayershofer, Rupert, Hofer, Jan-Hinnerk, Karch, Hans-Werner, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Heinrichs, Sophie K. M., Hess, Timo, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Mueller-Myhsok, Bertram, Ott, Katja, Schmidt, Thomas, Whiteman, David C., Vaughan, Thomas L., Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, Schumacher, Johannes, Becker, Jessica, May, Andrea, Gerges, Christian, Anders, Mario, Veits, Lothar, Weise, Katharina, Czamara, Darina, Lyros, Orestis, Manner, Hendrik, Terheggen, Grischa, Venerito, Marino, Noder, Tania, Mayershofer, Rupert, Hofer, Jan-Hinnerk, Karch, Hans-Werner, Ahlbrand, Constantin J., Arras, Michael, Hofer, Sebastian, Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Heinrichs, Sophie K. M., Hess, Timo, Kiesslich, Ralf, Izbicki, Jakob R., Hoelscher, Arnulf H., Bollschweiler, Elfriede, Malfertheiner, Peter, Lang, Hauke, Moehler, Markus, Lorenz, Dietmar, Mueller-Myhsok, Bertram, Ott, Katja, Schmidt, Thomas, Whiteman, David C., Vaughan, Thomas L., Noethen, Markus M., Hackelsberger, Andreas, Schumacher, Brigitte, Pech, Oliver, Vashist, Yogesh, Vieth, Michael, Weismueller, Josef, Neuhaus, Horst, Roesch, Thomas, Ell, Christian, Gockel, Ines, and Schumacher, Johannes
Abstract: The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P< 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P<10(-5)) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.
Published: 2015

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