TY  - JOUR
AU  - Hess, Timo
AU  - Maj, Carlo
AU  - Gehlen, Jan
AU  - Borisov, Oleg
AU  - Haas, Stephan L
AU  - Gockel, Ines
AU  - Vieth, Michael
AU  - Piessen, Guillaume
AU  - Alakus, Hakan
AU  - Vashist, Yogesh
AU  - Pereira, Carina
AU  - Knapp, Michael
AU  - Schüller, Vitalia
AU  - Quaas, Alexander
AU  - Grabsch, Heike I
AU  - Trautmann, Jessica
AU  - Malecka-Wojciesko, Ewa
AU  - Mokrowiecka, Anna
AU  - Speller, Jan
AU  - Mayr, Andreas
AU  - Schröder, Julia
AU  - Hillmer, Axel M
AU  - Heider, Dominik
AU  - Lordick, Florian
AU  - Pérez-Aísa, Ángeles
AU  - Campo, Rafael
AU  - Espinel, Jesús
AU  - Geijo, Fernando
AU  - Thomson, Concha
AU  - Bujanda, Luis
AU  - Sopeña, Federico
AU  - Lanas, Ángel
AU  - Pellisé, María
AU  - Pauligk, Claudia
AU  - Goetze, Thorsten Oliver
AU  - Zelck, Carolin
AU  - Reingruber, Julian
AU  - Hassanin, Emadeldin
AU  - Elbe, Peter
AU  - Alsabeah, Sandra
AU  - Lindblad, Mats
AU  - Nilsson, Magnus
AU  - Kreuser, Nicole
AU  - Thieme, René
AU  - Tavano, Francesca
AU  - Pastorino, Roberta
AU  - Arzani, Dario
AU  - Persiani, Roberto
AU  - Jung, Jin-On
AU  - Nienhüser, Henrik
AU  - Ott, Katja
AU  - Schumann, Ralf R
AU  - Kumpf, Oliver
AU  - Burock, Susen
AU  - Arndt, Volker
AU  - Jakubowska, Anna
AU  - Ławniczak, Małgorzta
AU  - Moreno, Victor
AU  - Martín, Vicente
AU  - Kogevinas, Manolis
AU  - Pollán, Marina
AU  - Dąbrowska, Justyna
AU  - Salas, Antonio
AU  - Cussenot, Olivier
AU  - Boland-Auge, Anne
AU  - Daian, Delphine
AU  - Deleuze, Jean-Francois
AU  - Salvi, Erika
AU  - Teder-Laving, Maris
AU  - Tomasello, Gianluca
AU  - Ratti, Margherita
AU  - Senti, Chiara
AU  - De Re, Valli
AU  - Steffan, Agostino
AU  - Hölscher, Arnulf H
AU  - Messerle, Katharina
AU  - Bruns, Christiane Josephine
AU  - Sīviņš, Armands
AU  - Bogdanova, Inga
AU  - Skieceviciene, Jurgita
AU  - Arstikyte, Justina
AU  - Moehler, Markus
AU  - Lang, Hauke
AU  - Grimminger, Peter P
AU  - Kruschewski, Martin
AU  - Vassos, Nikolaos
AU  - Schildberg, Claus
AU  - Lingohr, Philipp
AU  - Ridwelski, Karsten
AU  - Lippert, Hans
AU  - Fricker, Nadine
AU  - Krawitz, Peter
AU  - Hoffmann, Per
AU  - Nöthen, Markus M
AU  - Veits, Lothar
AU  - Izbicki, Jakob R
AU  - Mostowska, Adrianna
AU  - Martinón-Torres, Federico
AU  - Cusi, Daniele
AU  - Adolfsson, Rolf
AU  - Cancel-Tassin, Geraldine
AU  - Höblinger, Aksana
AU  - Rodermann, Ernst
AU  - Ludwig, Monika
AU  - Keller, Gisela
AU  - Metspalu, Andres
AU  - Brenner, Hermann
AU  - Heller, Joerg
AU  - Neef, Markus
AU  - Schepke, Michael
AU  - Dumoulin, Franz Ludwig
AU  - Hamann, Lutz
AU  - Cannizzaro, Renato
AU  - Ghidini, Michele
AU  - Plaßmann, Dominik
AU  - Geppert, Michael
AU  - Malfertheiner, Peter
AU  - Gehlen, Olivier
AU  - Skoczylas, Tomasz
AU  - Majewski, Marek
AU  - Lubiński, Jan
AU  - Palmieri, Orazio
AU  - Boccia, Stefania
AU  - Latiano, Anna
AU  - Aragones, Nuria
AU  - Schmidt, Thomas
AU  - Dinis-Ribeiro, Mário
AU  - Medeiros, Rui
AU  - Al-Batran, Salah-Eddin
AU  - Leja, Mārcis
AU  - Kupcinskas, Juozas
AU  - García-González, María A
AU  - Venerito, Marino
AU  - Schumacher, Johannes
TI  - Dissecting the genetic heterogeneity of gastric cancer.
JO  - EBioMedicine
VL  - 92
SN  - 2352-3964
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2023-01016
SP  - 104616
PY  - 2023
AB  - 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.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.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.Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.German Research Foundation (DFG).
KW  - Gastric cancer (Other)
KW  - Genome-wide association study (GWAS) (Other)
KW  - Oesophageal adenocarcinoma (Other)
KW  - Transcriptome-wide association study (TWAS) (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37209533
DO  - DOI:10.1016/j.ebiom.2023.104616
UR  - https://inrepo02.dkfz.de/record/276194
ER  -