Dissecting the genetic heterogeneity of gastric cancer

Hess T, Maj C, Gehlen J, Borisov O, Haas SL, Gockel I, Vieth M, Piessen G, Alakus H, Vashist Y, Pereira C, Knapp M, Schüller V, Quaas A, Grabsch HI, Trautmann J, Malecka-Wojciesko E, Mokrowiecka A, Speller J, Mayr A, Schröder J, Hillmer AM, Heider D, Lordick F, Pérez-Aísa Á, Campo R, Espinel J, Geijo F, Thomson C, Bujanda L, Sopeña F, Lanas Á, Pellisé M, Pauligk C, Goetze TO, Zelck C, Reingruber J, Hassanin E, Elbe P, Alsabeah S, Lindblad M, Nilsson M, Kreuser N, Thieme R, Tavano F, Pastorino R, Arzani D, Persiani R, Jung JO, Nienhüser H, Ott K, Schumann RR, Kumpf O, Burock S, Arndt V, Jakubowska A, Ławniczak M, Moreno V, Martín V, Kogevinas M, Pollán M, Dąbrowska J, Salas A, Cussenot O, Boland-Auge A, Daian D, Deleuze JF, Salvi E, Teder-Laving M, Tomasello G, Ratti M, Senti C, De Re V, Steffan A, Hölscher AH, Messerle K, Bruns CJ, Sīviņš A, Bogdanova I, Skieceviciene J, Arstikyte J, Moehler M, Lang H, Grimminger PP, Kruschewski M, Vassos N, Schildberg C, Lingohr P, Ridwelski K, Lippert H, Fricker N, Krawitz P, Hoffmann P, Nöthen MM, Veits L, Izbicki JR, Mostowska A, Martinón-Torres F, Cusi D, Adolfsson R, Cancel-Tassin G, Höblinger A, Rodermann E, Ludwig M, Keller G, Metspalu A, Brenner H, Heller J, Neef M, Schepke M, Dumoulin FL, Hamann L, Cannizzaro R, Ghidini M, Plaßmann D, Geppert M, Malfertheiner P, Gehlen O, Skoczylas T, Majewski M, Lubiński J, Palmieri O, Boccia S, Latiano A, Aragones N, Schmidt T, Dinis-Ribeiro M, Medeiros R, Al-Batran SE, Leja M, Kupcinskas J, García-González MA, Venerito M, Schumacher J (2023)

Publication Language: English

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 92

Article Number: 104616

DOI: 10.1016/j.ebiom.2023.104616

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 mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Authors with CRIS profile

Involved external institutions

Centro de Investigación Biomédica en Red - Enfermedades Hepáticas y Digestivas (CIBERHD) Spain (ES) Krankenhaus Nordwest Germany (DE) Philipps-Universität Marburg Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES) Spain (ES) Lithuanian University of Health Sciences / Lietuvos sveikatos mokslų universitetas (LSMU) Lithuania (LT) Klinikum Frankfurt (Oder) Germany (DE) Universitätsklinikum Mannheim Germany (DE) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Marienhaus Klinikum im Kreis Ahrweiler Germany (DE) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Universitätsklinikum Köln Germany (DE) Universitätsklinikum Bonn Germany (DE) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universitätsklinikum Leipzig Germany (DE) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP) Spain (ES) University of Santiago de Compostela / Universidad de Santiago de Compostela (USC) Spain (ES) Charité - Universitätsmedizin Berlin Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Duran i Reynals Hospital Spain (ES) National Center of Human Genomics Research / Centre National de Recherche en Génomique Humaine (CNRGH) France (FR) Foundation of the Carlo Besta Neurological Institute (IRCCS) Italy (IT) University of Tartu Estonia (EE) Istituti Ospitalieri di Cremona Italy (IT) Universität zu Köln Germany (DE) University of Latvia Latvia (LV) Medical University of Łódź / Uniwersytet Medyczny w Łodzi Poland (PL) Technische Universität München (TUM) Germany (DE) HELIOS Kliniken Germany (DE) Umeå University Sweden (SE) Otto-von-Guericke-Universität Magdeburg Germany (DE) Centre Hospitalier Lyon Sud (CHLS) France (FR) Medical University of Lublin / Uniwersytet Medyczny w Lublinie Poland (PL) Casa Sollievo della Sofferenza Italy (IT) Fondazione Policlinico Universitario Agostino Gemelli IRCCS Italy (IT) Gemeinschaftsklinikum Mittelrhein Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) RoMed Kliniken - Kliniken der Stadt und des Landkreises Rosenheim GmbH Germany (DE) Centro di Riferimento Oncologico (CRO) Italy (IT) Medizinische Hochschule Brandenburg "Theodor Fontane" / Brandenburg Medical School "Theodor Fontane" Germany (DE) Universidade do Porto Portugal (PT) Instituto Português de Oncologia do Porto FG, EPE (IPO-Porto) Portugal (PT) Centre for Research on Prostatic Diseases / CeRePP France (FR) Maastricht University Medical Center (UMC+) Netherlands (NL) Hospital Costa del Sol Spain (ES) Hospital Parc Tauli Spain (ES) Hospital de León Spain (ES) Complejo Hospitalario de Salamanca / Complejo Asistencial Universitario de Salamanca Spain (ES) Hospital Obispo Polanco Spain (ES) Klinikum Magdeburg Germany (DE) Institute of Biomedical Technologies / Istituto di Tecnologie Biomediche (CNR ITB) Italy (IT)

How to cite

APA:

Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S.L., Gockel, I.,... Schumacher, J. (2023). Dissecting the genetic heterogeneity of gastric cancer. EBioMedicine, 92. https://doi.org/10.1016/j.ebiom.2023.104616

MLA:

Hess, Timo, et al. "Dissecting the genetic heterogeneity of gastric cancer." EBioMedicine 92 (2023).

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