Format

Send to

Choose Destination
Gut. 2019 Aug 5. pii: gutjnl-2019-318760. doi: 10.1136/gutjnl-2019-318760. [Epub ahead of print]

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

Yan C1,2,3, Zhu M1,2, Ding Y4, Yang M5, Wang M6,7, Li G8, Ren C9, Huang T1, Yang W10, He B11, Wang M2,12, Yu F1, Wang J1, Zhang R6,7, Wang T1, Ni J1, Chen J1,2, Jiang Y1,2, Dai J1,2, Zhang E1,2, Ma H1,2, Wang Y13, Xu D13, Wang S2,11, Chen Y2,14, Xu Z2,15, Zhou J2,16, Ji G2,17, Wang Z18, Zhang Z2,12, Hu Z1,2,3, Wei Q6,19,20, Shen H1,2, Jin G21,2,3.

Author information

1
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
2
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
3
State Key Laboratory of Reproductive Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China.
4
Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou, China.
5
Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China.
6
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
7
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
8
Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
9
Department of Laboratory Medicine, Clinical Medical College of Yangzhou University, Yangzhou, China.
10
Key Laboratory of Fertility Preservation and Maintenance, The General Hospital, Ningxia Medical University, Yinchuan, China.
11
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nangjing, China.
12
Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
13
Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, Shanghai, China.
14
Department of Immunology, Nanjing Medical University, Nanjing, China.
15
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
16
Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
17
Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
18
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
19
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.
20
Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA.
21
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China guangfujin@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<5×10- 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.

KEYWORDS:

gene regulation; genetics; mutation; stomach cancer

PMID:
31383772
DOI:
10.1136/gutjnl-2019-318760

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center