بيانات النشر: UmeÃ¥ universitet, Institutionen för medicinsk biovetenskap
Umeå universitet, Institutionen för strålningsvetenskaper
Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States
Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States
Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States
Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Quebec City, Canada
Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France
Division of Cancer Epidemiology and Genetics, NCI, NIH, MD, Bethesda, Liberia
Department of Integrative Oncology, University of British Columbia, BC, Vancouver, Canada
Public Health Department, University of Oviedo, Asturias, Spain
Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States
Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany
Helmholtz-Munich Institute of Epidemiology, Neuherberg, Germany
Departments of Environmental Health and Epidemiology, Harvard TH Chan School of Public Health, MA, Boston, United States
Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
University of Kentucky, Markey Cancer Center, KY, Lexington, United States
Swedish Cancer Institute, WA, Seattle, United States
Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Department of Biostatistics, University of Texas, MD Anderson Cancer Center, TX, Houston, United States; Department of Epidemiology, University of Texas MD Anderson Cancer Center, TX, Houston, United States
Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States
University Health Network- The Princess Margaret Cancer Centre, CA, Toronto, United States
Luenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Canada
Departments of Epidemiology and Community and Family Medicine, Dartmouth College, Hanover, New Hampshire
Radboud University Medical Center, Nijmegen, Netherlands
Department of Biostatistics, University of Texas, MD Anderson Cancer Center, TX, Houston, United States
National Institute of Occupational Health, Oslo, Norway
Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
Department of Preventive Medicine, Seoul National University College of Medicine, Republic of South Korea, Seoul, South Korea
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, FL, Tampa, Puerto Rico
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, TN, Nashville, United States
Department of Oncology, Wayne State University School of Medicine, MI, Detroit, United States; Karmanos Cancer Institute, MI, Detroit, United States
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, MN, Rochester, United States
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States
National Human Genome Research Institute, NIH, MD, Baltimore, Liberia
University of Cincinnati College of Medicine, OH, Cincinnati, United States
Louisiana State University Health Sciences Center, LA, New Orleans, United States
College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio
Creighton University School of Medicine, NE, Omaha, United States
The University of Toledo College of Medicine, Toledo, Ohio
نبذة مختصرة : BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.
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