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<5×10− 8 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=4.56×10− 9) and 4q28.1 (OR=1.14, p=3.33×10− 11) 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
- gene regulation
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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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