Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.
mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk.



Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci.



This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association.



The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc.
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.|Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Fei
F
Zhou
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Yanru
Y
Wang
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Hongliang
H
Liu
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Neal
N
Ready
Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Younghun
Y
Han
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Rayjean J
RJ
Hung
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Yonathan
Y
Brhane
Public Health Ontario, Toronto, Ontario, Canada.
John
J
McLaughlin
Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
Paul
P
Brennan
Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Göttingen, Germany.
Heike
H
Bickeböller
Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Göttingen, Germany.
Albert
A
Rosenberger
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Richard S
RS
Houlston
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Neil
N
Caporaso
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Maria Teresa
MT
Landi
Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology I, Neuherberg, Germany.
Irene
I
Brüske
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Angela
A
Risch
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yuanqing
Y
Ye
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Xifeng
X
Wu
Massachusetts General Hospital, Boston, Massachusetts.|Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
David C
DC
Christiani
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Swedish Cancer Institute, Seattle, Washington.
Gary
G
Goodman
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Chu
C
Chen
Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Christopher I
CI
Amos
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Qingyi
Q
Wei
D005095:Exoribonucleases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*
D012333:RNA, Messenger; D005095:Exoribonucleases; C534418:cNOT6 protein, human
lung cancer risk; molecular epidemiology; pathway analysis