Fei Zhou1,2,3,4,5, Yanru Wang1,2, Hongliang Liu1,2, Neal Ready1,2, Younghun Han6, Rayjean J Hung7, Yonathan Brhane7, John McLaughlin8, Paul Brennan9, Heike Bickeböller10, Albert Rosenberger10, Richard S Houlston11, Neil Caporaso12, Maria Teresa Landi12, Irene Brüske13, Angela Risch14, Yuanqing Ye15, Xifeng Wu15, David C Christiani16,17, Gary Goodman18,19, Chu Chen18, Christopher I Amos6, Qingyi Wei1,2. 1. Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. 2. Department of Medicine, Duke University School of Medicine, Durham, North Carolina. 3. Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 4. Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China. 5. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. 6. Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. 7. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. 8. Public Health Ontario, Toronto, Ontario, Canada. 9. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France. 10. Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Göttingen, Germany. 11. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. 12. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 13. Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology I, Neuherberg, Germany. 14. Department of Molecular Biology, University of Salzburg, Salzburg, Austria. 15. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 16. Massachusetts General Hospital, Boston, Massachusetts. 17. Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts. 18. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 19. Swedish Cancer Institute, Seattle, Washington.
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: The CNOT6rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.
Authors: Christopher I Amos; Xifeng Wu; Peter Broderick; Ivan P Gorlov; Jian Gu; Timothy Eisen; Qiong Dong; Qing Zhang; Xiangjun Gu; Jayaram Vijayakrishnan; Kate Sullivan; Athena Matakidou; Yufei Wang; Gordon Mills; Kimberly Doheny; Ya-Yu Tsai; Wei Vivien Chen; Sanjay Shete; Margaret R Spitz; Richard S Houlston Journal: Nat Genet Date: 2008-04-02 Impact factor: 38.330
Authors: Pengyuan Liu; Haris G Vikis; Daolong Wang; Yan Lu; Yian Wang; Ann G Schwartz; Susan M Pinney; Ping Yang; Mariza de Andrade; Gloria M Petersen; Jonathan S Wiest; Pamela R Fain; Adi Gazdar; Colette Gaba; Henry Rothschild; Diptasri Mandal; Teresa Coons; Juwon Lee; Elena Kupert; Daniela Seminara; John Minna; Joan E Bailey-Wilson; Xifeng Wu; Margaret R Spitz; Timothy Eisen; Richard S Houlston; Christopher I Amos; Marshall W Anderson; Ming You Journal: J Natl Cancer Inst Date: 2008-09-09 Impact factor: 13.506
Authors: Tuuli Lappalainen; Michael Sammeth; Marc R Friedländer; Peter A C 't Hoen; Jean Monlong; Manuel A Rivas; Mar Gonzàlez-Porta; Natalja Kurbatova; Thasso Griebel; Pedro G Ferreira; Matthias Barann; Thomas Wieland; Liliana Greger; Maarten van Iterson; Jonas Almlöf; Paolo Ribeca; Irina Pulyakhina; Daniela Esser; Thomas Giger; Andrew Tikhonov; Marc Sultan; Gabrielle Bertier; Daniel G MacArthur; Monkol Lek; Esther Lizano; Henk P J Buermans; Ismael Padioleau; Thomas Schwarzmayr; Olof Karlberg; Halit Ongen; Helena Kilpinen; Sergi Beltran; Marta Gut; Katja Kahlem; Vyacheslav Amstislavskiy; Oliver Stegle; Matti Pirinen; Stephen B Montgomery; Peter Donnelly; Mark I McCarthy; Paul Flicek; Tim M Strom; Hans Lehrach; Stefan Schreiber; Ralf Sudbrak; Angel Carracedo; Stylianos E Antonarakis; Robert Häsler; Ann-Christine Syvänen; Gert-Jan van Ommen; Alvis Brazma; Thomas Meitinger; Philip Rosenstiel; Roderic Guigó; Ivo G Gut; Xavier Estivill; Emmanouil T Dermitzakis Journal: Nature Date: 2013-09-15 Impact factor: 49.962