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Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations
  1. Caiwang Yan1,2,3,
  2. Meng Zhu1,2,
  3. Yanbing Ding4,
  4. Ming Yang5,
  5. Mengyun Wang6,7,
  6. Gang Li8,
  7. Chuanli Ren9,
  8. Tongtong Huang1,
  9. Wenjun Yang10,
  10. Bangshun He11,
  11. Meilin Wang2,12,
  12. Fei Yu1,
  13. Jinchen Wang1,
  14. Ruoxin Zhang6,7,
  15. Tianpei Wang1,
  16. Jing Ni1,
  17. Jiaping Chen1,2,
  18. Yue Jiang1,2,
  19. Juncheng Dai1,2,
  20. Erbao Zhang1,2,
  21. Hongxia Ma1,2,
  22. Yanong Wang13,
  23. Dazhi Xu13,
  24. Shukui Wang2,11,
  25. Yun Chen2,14,
  26. Zekuan Xu2,15,
  27. Jianwei Zhou2,16,
  28. Guozhong Ji2,17,
  29. Zhaoming Wang18,
  30. Zhengdong Zhang2,12,
  31. Zhibin Hu1,2,3,
  32. Qingyi Wei6,19,20,
  33. Hongbing Shen1,2,
  34. Guangfu Jin1,2,3
  1. 1Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
  2. 2Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
  3. 3State Key Laboratory of Reproductive Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
  4. 4Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou, China
  5. 5Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China
  6. 6Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
  7. 7Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
  8. 8Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
  9. 9Department of Laboratory Medicine, Clinical Medical College of Yangzhou University, Yangzhou, China
  10. 10Key Laboratory of Fertility Preservation and Maintenance, The General Hospital, Ningxia Medical University, Yinchuan, China
  11. 11General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nangjing, China
  12. 12Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
  13. 13Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, Shanghai, China
  14. 14Department of Immunology, Nanjing Medical University, Nanjing, China
  15. 15Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  16. 16Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
  17. 17Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  18. 18Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
  19. 19Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
  20. 20Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA
  1. Correspondence to Dr Guangfu Jin, Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; guangfujin{at}njmu.edu.cn

Abstract

Objective Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development.

Design We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies.

Results The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×108 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×109) and 4q28.1 (OR=1.14, p=3.33×1011) were associated with GC risk.

Conclusion We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

  • stomach cancer
  • genetics
  • mutation
  • gene regulation
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Footnotes

  • CY, MZ, YD, MY, MW, GL and CR are joint first authors.

  • Correction notice This article has been corrected since it published Online First. An author note has been added.

  • Contributors GuaJ, HS, QW and ZH designed the study and edited the manuscript; CY and MZ performed statistical analysis, conducted experiments and wrote the manuscript; TH, FY, JW, TW, JN, JC and YJ performed the genotyping and experiments; YD, MY, MenW, GL, CR, WY, BH and MeiW, RZ, YW and DX contributed to sample collection; EZ, JD, HM, SW, YC, ZX, JZ, GuoJ, ZW and ZZ reviewed data and provided critical comments or suggestions; GuaJ had primary responsibility for final content.

  • Funding This work was supported by grants from the National Major Research and Development Programme (2016YFC1302703); National Natural Science Foundation of China (81872702, 81521004 and 81573228); 333 High-Level Talents Cultivation Project of Jiangsu Province (BRA2018057); Jiangsu Outstanding Youth Fund (BK20160095); Project funded by China Postdoctoral Science Foundation (2019TQ0157).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Review Board of Nanjing Medical University. Animal care and handling procedures were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and were approved by the Committee on the Ethics of Animal Experiments of Nanjing Medical University (Nanjing, China).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

  • Author note Dr Qingyi Wei is a visiting professor at Fudan University.

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