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Dissecting the genetic heterogeneity of gastric cancer

2023; Elsevier BV; Volume: 92; Linguagem: Inglês

10.1016/j.ebiom.2023.104616

2352-3964

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

Genetic Associations and Epidemiology

BackgroundGastric 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.MethodsWe 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.FindingsOur 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.InterpretationOur 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.FundingGerman Research Foundation (DFG).