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Dissecting the genetic heterogeneity of gastric cancer

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dc.contributor.author Hess, Timo
dc.contributor.author Kogevinas, Manolis
dc.contributor.author Schumacher, Johannes
dc.date.accessioned 2023-07-04T06:42:28Z
dc.date.available 2023-07-04T06:42:28Z
dc.date.issued 2023
dc.identifier.citation Hess T, Maj C, Gehlen J, Borisov O, Haas SL, Gockel I, et al. Dissecting the genetic heterogeneity of gastric cancer. EBioMedicine. 2023 Jun;92:104616. DOI: 10.1016/j.ebiom.2023.104616
dc.identifier.issn 2352-3964
dc.identifier.uri http://hdl.handle.net/10230/57453
dc.description.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).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof EBioMedicine. 2023 Jun;92:104616
dc.rights © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.title Dissecting the genetic heterogeneity of gastric cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.ebiom.2023.104616
dc.subject.keyword Gastric cancer
dc.subject.keyword Genome-wide association study (GWAS)
dc.subject.keyword Oesophageal adenocarcinoma
dc.subject.keyword Transcriptome-wide association study (TWAS)
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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