Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations

Abstract

ObjectiveAlthough 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.DesignWe 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.ResultsThe 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.ConclusionWe 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.

Helicobacter pylorieradication therapy to prevent gastric cancer: systematic review and meta-analysis

“…[3] Infection with the bacterium causes chronic gastritis. [4] In a minority of susceptible individuals, [5] this can lead to a stepwise progression through gastric atrophy, intestinal metaplasia, and dysplasia, to the development of carcinoma. [6] As a result, H.…”

Incorporating family disease history and controlling case-control imbalance for population based genetic association studies

“…For gastric cancer (case:control=1:191), both TAPE and TAPE-LTFH identified 3 genome-wide significant clumped variants (rs760077, rs35972942, rs2978977) while no variants were genome-wide significant by SAIGE. The three clumped variants have been previously reported to be associated with gastric cancer among Chinese or Japanese population [22][23][24] , but not among Korean samples. Manhattan plots and Q-Q plots are presented in Supplementary Figures 10 and 11.…”

The Identification of RNA Modification Gene PUS7 as a Potential Biomarker of Ovarian Cancer

“…To rationalize the vital role of PUS7 in OV, we explored the proteins interacting with PUS7, which may partially help explain PUS7 function in tumor diagnosis, tumorigenesis, and development. The PPI and gene network analyses identified PUS7 interacting partners, including NOC3L and PUS1, which are also not reported in ovarian cancer, although several reports have revealed that NOC3L regulates the proliferation and tumorigenesis of gastric cancer [ 41 ], and NOC3L is associated with an increased risk of gastric cancer in the Chinese Han population [ 42 ]. For PUS1, previous reports demonstrated that it is related to sideroblastic anemia [ 43 ], and no association of PUS1 with cancer was ever shown, suggesting the novelty of the protein interaction.…”