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@ARTICLE{Hess:276194,
      author       = {T. Hess and C. Maj and J. Gehlen and O. Borisov and S. L.
                      Haas and I. Gockel and M. Vieth and G. Piessen and H. Alakus
                      and Y. Vashist and C. Pereira and M. Knapp and V. Schüller
                      and A. Quaas and H. I. Grabsch and J. Trautmann and E.
                      Malecka-Wojciesko and A. Mokrowiecka and J. Speller and A.
                      Mayr and J. Schröder and A. M. Hillmer and D. Heider and F.
                      Lordick and Á. Pérez-Aísa and R. Campo and J. Espinel and
                      F. Geijo and C. Thomson and L. Bujanda and F. Sopeña and
                      Á. Lanas and M. Pellisé and C. Pauligk and T. O. Goetze
                      and C. Zelck and J. Reingruber and E. Hassanin and P. Elbe
                      and S. Alsabeah and M. Lindblad and M. Nilsson and N.
                      Kreuser and R. Thieme and F. Tavano and R. Pastorino and D.
                      Arzani and R. Persiani and J.-O. Jung and H. Nienhüser and
                      K. Ott and R. R. Schumann and O. Kumpf and S. Burock and V.
                      Arndt$^*$ and A. Jakubowska and M. Ławniczak and V. Moreno
                      and V. Martín and M. Kogevinas and M. Pollán and J.
                      Dąbrowska and A. Salas and O. Cussenot and A. Boland-Auge
                      and D. Daian and J.-F. Deleuze and E. Salvi and M.
                      Teder-Laving and G. Tomasello and M. Ratti and C. Senti and
                      V. De Re and A. Steffan and A. H. Hölscher and K. Messerle
                      and C. J. Bruns and A. Sīviņš and I. Bogdanova and J.
                      Skieceviciene and J. Arstikyte and M. Moehler and H. Lang
                      and P. P. Grimminger and M. Kruschewski and N. Vassos and C.
                      Schildberg and P. Lingohr and K. Ridwelski and H. Lippert
                      and N. Fricker and P. Krawitz and P. Hoffmann and M. M.
                      Nöthen and L. Veits and J. R. Izbicki and A. Mostowska and
                      F. Martinón-Torres and D. Cusi and R. Adolfsson and G.
                      Cancel-Tassin and A. Höblinger and E. Rodermann and M.
                      Ludwig and G. Keller and A. Metspalu and H. Brenner$^*$ and
                      J. Heller and M. Neef and M. Schepke and F. L. Dumoulin and
                      L. Hamann and R. Cannizzaro and M. Ghidini and D. Plaßmann
                      and M. Geppert and P. Malfertheiner and O. Gehlen and T.
                      Skoczylas and M. Majewski and J. Lubiński and O. Palmieri
                      and S. Boccia and A. Latiano and N. Aragones and T. Schmidt
                      and M. Dinis-Ribeiro and R. Medeiros and S.-E. Al-Batran and
                      M. Leja and J. Kupcinskas and M. A. García-González and M.
                      Venerito and J. Schumacher},
      title        = {{D}issecting the genetic heterogeneity of gastric cancer.},
      journal      = {EBioMedicine},
      volume       = {92},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-01016},
      pages        = {104616},
      year         = {2023},
      abstract     = {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).},
      keywords     = {Gastric cancer (Other) / Genome-wide association study
                      (GWAS) (Other) / Oesophageal adenocarcinoma (Other) /
                      Transcriptome-wide association study (TWAS) (Other)},
      cin          = {C071 / C070 / C120 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)C071-20160331 / I:(DE-He78)C070-20160331 /
                      I:(DE-He78)C120-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37209533},
      doi          = {10.1016/j.ebiom.2023.104616},
      url          = {https://inrepo02.dkfz.de/record/276194},
}