期刊
NPJ PRECISION ONCOLOGY
卷 6, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41698-022-00281-9
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资金
- National Natural Science Foundation of China (NSFC) [82160535, 81902876]
- Ningxia Natural Science Foundation [2022AAC03544]
- Hainan Province Clinical Medical Center
- Cancer Care Ontario Research Chair of Population Studies
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System
- Canadian Cancer Society Research Institute [020214]
- Ontario Institute of Cancer
- Cancer Research UK [C1298/A8780, C1298/A8362]
- NCRN
- NIH [5R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, U19-CA148127, P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753, HHSN268200782096C]
- Roy Castle Lung Cancer Foundation, UK
- Deutsche Krebshilfe [70-2919]
- Helmholtz-DAAD fellowship [A/07/97379]
- GSF - German Federal Ministry of Education, Science, Research and Technology
- National Genome Research Network (NGFN)
- DFG [BI576/2-1, BI 576/2-2]
- Helmholtzgemeinschaft (HGF)
- Federal office for Radiation Protection [BfS: STSch4454]
- Institute National du Cancer, France
- European Community [LSHG-CT-2005-512113]
- Norwegian Cancer Association
- Functional Genomics Program of Research Council of Norway
- European Regional Development Fund
- State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]
- US National Cancer Institute, NIH [R01 CA111703, UO1 CA63673]
- Fred Hutchinson Cancer Research Center
- US National Cancer Institute [R01 CA092039]
- IARC
- Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics
- US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]
- NCI [NO1-CN-25514, NO1-CN25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]
- American Cancer Society
- NIH Genes, Environment and Health Initiative (GEI) [HG06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]
- CPRIT grant [RP100443]
- NIH (National Cancer Institute) [CA092824, CA090578, CA074386]
- National Institutes of Health Feasibility and Planning Studies for Development of Specialized Programs of Research Excellence (SPOREs) [1P20CA251657-01]
- National Institutes of Health [GENADDICT: LSHMCT-2004-005166, R01-DA017932]
- Center for Inherited Disease Research [26820120008i-0-26800068-1]
- Cancer Care Ontario Chair Award
- HEAL
- SanoAventis
- State of Bavaria
- [U19-CA203654]
- [CA148127]
- [CA148127S1]
- [RR170048]
Limited efforts have been made in assessing the impact of genome-wide profiling of RNA splicing-related variation on lung cancer risk. This study identified three genetic variants related to RNA splicing that significantly contribute to lung cancer susceptibility in European populations. Validation and exploration of specific splicing mechanisms underlying these associations are needed.
Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E-09), rs2285521 in GGA2 (P = 4.43E-08), and rs198459 in MYRF (P = 1.60E-06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E-08, P = 6.21E-08, and P = 7.93E-04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E-05, P = 2.70E-04, and P = 2.90E-05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.
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