Identification of risk genes for gastric cancer
Final Report Abstract
The main aim of the project was a GC GWAS meta-analysis using 4,000 patients and 6,000 controls for the identification of genetic risk variants and corresponding secondary analyses. However, for the following reasons the project was considerably more time-consuming than expected. However, the applicants have used the delay to carry out a more powerful study than initially planned: (i) They established collaborations with other European groups, increasing the GWAS sample size to 5,815 patients and 10,999 controls. (ii) In addition, tissue samples were collected from gastric corpus and antrum mucosa from 361 and 342 subjects. These tissues were used for a transcriptome-wide expression study in order to carry out powerful TWAS and eQTL studies along with the GC GWAS data. The GWAS meta-analysis lead to the identification of two genome-wide associated GC risk loci that have been reported previously. However, the present study showed for the first time that both loci are particularly strong associated to the subtype of non-cardia GC. In addition, two new genome-wide significant associated risk loci could be identified that contribute considerably stronger to the subtype intestinal GC. Moreover, two further risk loci that showed previous association in the East-Asian population could be replicated in the range of suggestive GC-association. The TWAS and eQTL study lead to the identification of GC risk genes at four of the six mentioned loci, three of these genes have not previously reported. Moreover, this GC GWAS meta-analysis represents the first that analyzed their data on the polygenic level. Here, we could identify that GC risk factors that have been identified in observational studies are also genetically correlated. In addition, we show for the first time that cardia GC located at the distal gastro-esophageal junction (GEJ) share genetic etiology with esophageal adenocarcinoma (EAC) located at the proximal GEJ. A joint GWAS meta-analysis of cardia GC and EAC resulted in the identification of two new risk loci for esophago-gastric adenocarcinomas. However, the data from the GC GWAS meta-analysis are the subject of many other analyses that are currently being carried out or will be carried out in near future. These include a sex-specific GC GWAS meta-analysis, a cross-population meta-analysis using GWAS data from the East-Asian population, and a comparison of the GWAS data with GWAS data on HP infection. Finally, the applicants plan a 2nd stage European GC GWAS meta-analysis with a patient sample that is twice as large as the 1st stage GWAS sample. Here, the majority of cases have already been recruited within this project.
Publications
- (2018) Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level. Cancer Med 7: 5057-5065
Heinrichs SKM, Hess T, Becker J, Hamann L, Vashist YK, Butterbach K, Schmidt T, Alakus H, Krasniuk I, Höblinger A, Lingohr P, Ludwig M, Hagel AF, Schildberg CW, Veits L, Gyvyte U, Weise K, Schüller V, Böhmer AC, Schröder J, Gehlen J, Kreuser N, Hofer S, Lang H, Lordick F, Malfertheiner P, Moehler M, Pech O, Vassos N, Rodermann E, Izbicki JR, Kruschewski M, Ott K, Schumann RR, Vieth M, Mangold E, Gasenko E, Kupcinskas L, Brenner H, Grimminger P, Bujanda L, Sopeña F, Espinel J, Thomson C, Pérez-Aísa Á, Campo R, Geijo F, Collette D, Bruns C, Messerle K, Gockel I, Nöthen MM, Lippert H, Ridwelski K, Lanas A, Keller G, Knapp M, Leja M, Kupcinskas J, García-González MA, Venerito M, Schumacher J
(See online at https://doi.org/10.1002/cam4.1719) - (2020) Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research. United European Gastroenterol J 8: 175-184
Weise F, Vieth M, Reinhold D, Haybaeck J, Goni E, Lippert H, Ridwelski K, Lingohr P, Schildberg C, Vassos N, Kruschewski M, Krasniuk I, Grimminger PP, Waidmann O, Peitz U, Veits L, Kreuser N, Lang H, Bruns C, Moehler M, Lordick F, Gockel I, Schumacher J, Malfertheiner P, Venerito M
(See online at https://doi.org/10.1177/2050640619891580) - (2021) Different Prevalence of Alarm, Dyspeptic and Reflux Symptoms in Patients with Cardia and Non-cardia Gastric Cancer. J Gastrointestin Liver Dis 30: 431-437
Franck C, Zimmermann N, Goni E, Lippert H, Ridwelski K, Kruschewski M, Kreuser N, Lingohr P, Schildberg C, Vassos N, Waidmann O, Peitz U, Lang H, Grmminger PP, Bruns C, Veits L, Vieth M, Moehler M, Lordick F, Gockel I, Schumacher J, Malfertheiner P, Venerito M
(See online at https://doi.org/10.15403/jgld-3795) - (2022) Clinical Relevance of Gastroesophageal Cancer Associated SNPs for Oncologic Outcome After Curative Surgery. Ann Surg Oncol 29: 1453-1462
Jung JO, Wirsik NM, Nienhüser H, Peters L, Müller-Stich BP, Hess T, Schüller V, Schumacher J, Schmidt T
(See online at https://doi.org/10.1245/s10434-021-10771-y) - (2022) Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort 1 and a meta-analysis. J Cancer Res Clin Oncol
Stolze T, Franke S, Haybaeck J, Moehler M, Grimminger PP, Lang H, Roth W, Gockel I, Kreuser N, Bläker H, Wittekind C, Lordick F, Vieth M, Veits L, Waidmann O, Lingohr P, Peitz U, Schildberg C, Kruschewski M, Vassos N, Goni E, Bruns CJ, Ridwelski K, Wolff S, Lippert H, Schumacher J, Malfertheiner P, Venerito M
(See online at https://doi.org/10.1007/s00432-022-03953-y)
