Dissecting the genetic heterogeneity of gastric cancer

Timo Hess; Carlo Maj; Jan Gehlen; Oleg Borisov; Stephan L. Haas; Ines Gockel; Michael Vieth; Guillaume Piessen; Hakan Alakus; Yogesh Vashist; Carina Pereira; Michael Knapp; Vitalia Schueller; Alexander Quaas; Heike I. Grabsch; Jessica Trautmann; Ewa Malecka-Wojciesko; Anna Mokrowiecka; Jan Speller; Andreas Mayr; Julia Schroeder; Axel M. Hillmer; Dominik Heider; Florian Lordick; Angeles Perez-Aisa; Rafael Campo; Jesus Espinel; Fernando Geijo; Concha Thomson; Luis Bujanda; Federico Sopena; Angel Lanas; Maria Pellise; Claudia Pauligk; Thorsten Oliver Goetze; Carolin Zelck; Julian Reingruber; Emadeldin Hassanin; Peter Elbe; Sandra Alsabeah; Mats Lindblad; Magnus Nilsson; Nicole Kreuser; Rene Thieme; Francesca Tavano; Roberta Pastorino; Dario Arzani; Roberto Persiani; Jin-On Jung; Henrik Nienhueser; Katja Ott; Johannes Schumacher

doi:10.1016/j.ebiom.2023.104616

Dissecting the genetic heterogeneity of gastric cancer

Timo Hess, Carlo Maj, Jan Gehlen, Oleg Borisov, Stephan L. Haas, Ines Gockel, Michael Vieth, Guillaume Piessen, Hakan Alakus, Yogesh Vashist, Carina Pereira, Michael Knapp, Vitalia Schueller, Alexander Quaas, Heike I. Grabsch, Jessica Trautmann, Ewa Malecka-Wojciesko, Anna Mokrowiecka, Jan Speller, Andreas MayrJulia Schroeder, Axel M. Hillmer, Dominik Heider, Florian Lordick, Angeles Perez-Aisa, Rafael Campo, Jesus Espinel, Fernando Geijo, Concha Thomson, Luis Bujanda, Federico Sopena, Angel Lanas, Maria Pellise, Claudia Pauligk, Thorsten Oliver Goetze, Carolin Zelck, Julian Reingruber, Emadeldin Hassanin, Peter Elbe, Sandra Alsabeah, Mats Lindblad, Magnus Nilsson, Nicole Kreuser, Rene Thieme, Francesca Tavano, Roberta Pastorino, Dario Arzani, Roberto Persiani, Jin-On Jung, Henrik Nienhueser, Katja Ott, Johannes Schumacher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopa-thology (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). Copyright & COPY; 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/).

Original language	English
Article number	104616
Number of pages	13
Journal	EBioMedicine
Volume	92
Issue number	1
Early online date	1 May 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104616
Publication status	Published - 1 Jun 2023

Keywords

Gastric cancer
Oesophageal adenocarcinoma
Genome-wide association study (GWAS)
Transcriptome-wide association study (TWAS)
GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
ESOPHAGEAL ADENOCARCINOMA
RISK
METAANALYSIS
VARIANTS
IDENTIFICATION

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1 Erratum / corrigendum / retractions

Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer” (eBioMedicine (2023) 92, (S2352396423001810), (10.1016/j.ebiom.2023.104616))
Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schüller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J. & Mayr, A. & 33 others, Schröder, J., Hillmer, A. M., 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, T. O., 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, J. O., Nienhüser, H., Ott, K., Schumacher, J. & Et al., 1 Aug 2023, In: EBioMedicine. 94, 4 p., 104709.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schueller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J., ... Schumacher, J. (2023). Dissecting the genetic heterogeneity of gastric cancer. EBioMedicine, 92(1), Article 104616. https://doi.org/10.1016/j.ebiom.2023.104616

@article{7d448c7c552e43a6b004b13211f1e753,

title = "Dissecting the genetic heterogeneity of gastric cancer",

abstract = "Background Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopa-thology (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). Copyright & COPY; 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/).",

keywords = "Gastric cancer, Oesophageal adenocarcinoma, Genome-wide association study (GWAS), Transcriptome-wide association study (TWAS), GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, ESOPHAGEAL ADENOCARCINOMA, RISK, METAANALYSIS, VARIANTS, IDENTIFICATION",

author = "Timo Hess and Carlo Maj and Jan Gehlen and Oleg Borisov and Haas, {Stephan L.} and Ines Gockel and Michael Vieth and Guillaume Piessen and Hakan Alakus and Yogesh Vashist and Carina Pereira and Michael Knapp and Vitalia Schueller and Alexander Quaas and Grabsch, {Heike I.} and Jessica Trautmann and Ewa Malecka-Wojciesko and Anna Mokrowiecka and Jan Speller and Andreas Mayr and Julia Schroeder and Hillmer, {Axel M.} and Dominik Heider and Florian Lordick and Angeles Perez-Aisa and Rafael Campo and Jesus Espinel and Fernando Geijo and Concha Thomson and Luis Bujanda and Federico Sopena and Angel Lanas and Maria Pellise and Claudia Pauligk and Goetze, {Thorsten Oliver} and Carolin Zelck and Julian Reingruber and Emadeldin Hassanin and Peter Elbe and Sandra Alsabeah and Mats Lindblad and Magnus Nilsson and Nicole Kreuser and Rene Thieme and Francesca Tavano and Roberta Pastorino and Dario Arzani and Roberto Persiani and Jin-On Jung and Henrik Nienhueser and Katja Ott and Johannes Schumacher",

year = "2023",

month = jun,

day = "1",

doi = "10.1016/j.ebiom.2023.104616",

language = "English",

volume = "92",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

number = "1",

}

Hess, T, Maj, C, Gehlen, J, Borisov, O, Haas, SL, Gockel, I, Vieth, M, Piessen, G, Alakus, H, Vashist, Y, Pereira, C, Knapp, M, Schueller, V, Quaas, A, Grabsch, HI, Trautmann, J, Malecka-Wojciesko, E, Mokrowiecka, A, Speller, J, Mayr, A, Schroeder, J, Hillmer, AM, Heider, D, Lordick, F, Perez-Aisa, A, Campo, R, Espinel, J, Geijo, F, Thomson, C, Bujanda, L, Sopena, F, Lanas, A, Pellise, 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, J-O, Nienhueser, H, Ott, K & Schumacher, J 2023, 'Dissecting the genetic heterogeneity of gastric cancer', EBioMedicine, vol. 92, no. 1, 104616. https://doi.org/10.1016/j.ebiom.2023.104616

TY - JOUR

T1 - Dissecting the genetic heterogeneity of gastric cancer

AU - Hess, Timo

AU - Maj, Carlo

AU - Gehlen, Jan

AU - Borisov, Oleg

AU - Haas, Stephan L.

AU - Gockel, Ines

AU - Vieth, Michael

AU - Piessen, Guillaume

AU - Alakus, Hakan

AU - Vashist, Yogesh

AU - Pereira, Carina

AU - Knapp, Michael

AU - Schueller, Vitalia

AU - Quaas, Alexander

AU - Grabsch, Heike I.

AU - Trautmann, Jessica

AU - Malecka-Wojciesko, Ewa

AU - Mokrowiecka, Anna

AU - Speller, Jan

AU - Mayr, Andreas

AU - Schroeder, Julia

AU - Hillmer, Axel M.

AU - Heider, Dominik

AU - Lordick, Florian

AU - Perez-Aisa, Angeles

AU - Campo, Rafael

AU - Espinel, Jesus

AU - Geijo, Fernando

AU - Thomson, Concha

AU - Bujanda, Luis

AU - Sopena, Federico

AU - Lanas, Angel

AU - Pellise, Maria

AU - Pauligk, Claudia

AU - Goetze, Thorsten Oliver

AU - Zelck, Carolin

AU - Reingruber, Julian

AU - Hassanin, Emadeldin

AU - Elbe, Peter

AU - Alsabeah, Sandra

AU - Lindblad, Mats

AU - Nilsson, Magnus

AU - Kreuser, Nicole

AU - Thieme, Rene

AU - Tavano, Francesca

AU - Pastorino, Roberta

AU - Arzani, Dario

AU - Persiani, Roberto

AU - Jung, Jin-On

AU - Nienhueser, Henrik

AU - Ott, Katja

AU - Schumacher, Johannes

PY - 2023/6/1

Y1 - 2023/6/1

N2 - Background Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopa-thology (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). Copyright & COPY; 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/).

AB - Background Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopa-thology (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). Copyright & COPY; 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/).

KW - Gastric cancer

KW - Oesophageal adenocarcinoma

KW - Genome-wide association study (GWAS)

KW - Transcriptome-wide association study (TWAS)

KW - GENOME-WIDE ASSOCIATION

KW - SUSCEPTIBILITY LOCI

KW - ESOPHAGEAL ADENOCARCINOMA

KW - RISK

KW - METAANALYSIS

KW - VARIANTS

KW - IDENTIFICATION

U2 - 10.1016/j.ebiom.2023.104616

DO - 10.1016/j.ebiom.2023.104616

M3 - Article

C2 - 37209533

SN - 2352-3964

VL - 92

JO - EBioMedicine

JF - EBioMedicine

IS - 1

M1 - 104616

ER -

Dissecting the genetic heterogeneity of gastric cancer

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Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer” (eBioMedicine (2023) 92, (S2352396423001810), (10.1016/j.ebiom.2023.104616))

Cite this