Dataset Information

Dissecting the genetic heterogeneity of gastric cancer.

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).

SUBMITTER: Hess T

PROVIDER: S-EPMC10212786 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Dissecting the genetic heterogeneity of gastric cancer.

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

EBioMedicine 20230518

<h4>Background</h4>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.<h4>Methods</h4>We did a meta-a ...[more]

PMID: 37209533

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Dataset Information

Dissecting the genetic heterogeneity of gastric cancer.

Background

Methods

Findings

Interpretation

Funding

Publications

Dissecting the genetic heterogeneity of gastric cancer.

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