Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Biobank and Tumor Documentation Thoraxklinik at University Hospital Heidelberg Heidelberg Germany

Biomedical Data Science Department Dartmouth College Hanover NH USA

Cancer Center Cluster Salzburg at PLUS Department of Molecular Biology University of Salzburg Salzburg Austria

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen Denmark

Department for Health Evidence Radboud University Medical Center Nijmegen EZ Netherlands

Department of Cancer Epidemiology and Prevention M Sklodowska Curie Cancer Center Institute of Oncology Warsaw Pol

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Science University of Bergen Bergen Norway

Department of Clinical Sciences and Community Health DISCCO University of Milan Milan Italy

Department of Clinical Sciences Lund University Lund Sweden

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lódz Pol

Department of Epidemiology and Biostatistics Imperial College London St Mary's Campus London UK

Department of Epidemiology and Biostatistics School of Medicine Case Western Reserve University Cleveland OH USA

Department of Epidemiology and Prevention Russian N N Blokhin Cancer Research Centre Moscow Russia

Department of Epidemiology Harvard School of Public Health Boston MA USA

Department of Epidemiology Norris Cotton Cancer Center Dartmouth College Hanover NH USA

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Genetic Epidemiology Medical School Georg August University of Göttingen Göttingen Germany

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen Göttingen Germany

Department of Health Sciences Genetic Epidemiology Group University of Leicester Leicester UK

Department of Hygiene and Epidemiology Medical School University of Athens Athens Greece

Department of Integrative Oncology British Columbia Cancer Research Centre Vancouver BC Canada

Department of Internal Medicine Skåne University Hospital Malmö Sweden

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Medicine The Princess Margaret Cancer Center University Health Network Toronto ON Canada

Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool UK

Department of Oncology Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen University Herlev Denmark

Department of Oncology University of Sheffield Sheffield UK

Department of Pharmaceutical Sciences College of Pharmacy Washington State University Spokane WA USA

Department of Preventive Medicine IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico University of Milan Milan Italy

Department of Radiation Sciences Umeå University Umeå Sweden

Department of Thoracic Oncology H Lee Moffitt Cancer Center Tampa FL USA

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville TN USA

Department of Thoracic Surgery National Institute of Tuberculosis and Lung Diseases Warsaw Pol

Department of Toxicology National Institute of Occupational Health Oslo Norway

Division of Cancer Epidemiology and Genetics National Cancer Institute US National Institutes of Health Bethesda MD USA

Division of Epidemiology Dalla Lana School of Public Health University of Toronto Lunenfeld Tanenbaum Research Institute Toronto Ontario Canada

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Genetic Epidemiology Group Department of Health Sciences Leicester Respiratory Biomedical Research Unit Glenfield Hospital Leicester UK

Genetic Epidemiology School of Health and Related Research University of Sheffield Sheffield UK

Institute of Epidemiology Helmholtz Centre Munich Neuherberg Germany

Institute of Translational Medicine University of Liverpool Liverpool UK

Internal Medicine School of Medicine Clinical Center of Serbia University of Belgrade Belgrade Serbia

International Agency for Research on Cancer Genetic Epidemiology Group Lyon France

International Agency for Research on Cancer World Health Organization Lyon France

International Organization for Cancer Prevention and Research Belgrade Serbia

Markey Cancer Center University of Kentucky Lexington KY USA

Medical Oncology Toronto Princess Margaret Hospital Toronto ON Canada

Medicina IUOPA Universidad de Oviedo Oviedo Spain

Molecular and Nutritional Epidemiology Unit CSPO Scientific Institute of Tuscany Florence Italy

Princess Margaret Cancer Centre Toronto ON M5G Canada

Public Health Sciences Division Cancer Prevention Program Swedish Medical Center Seattle WA USA

Public Health Sciences Division Program in Epidemiology Fred Hutchinson Cancer Research Center Seattle WA USA

Section for Epidemiology Department of Public Health Aarhus University Aarhus C Denmark

Technion Faculty of Medicine Clalit National Cancer Control Center Carmel Medical Center Haifa Israel

The Institute of Cancer Research London UK

Thoracic Surgery Division Marius Nasta National Institute of Pneumology Bucure?ti Romania

Translational Lung Research Center Heidelberg Heidelberg Germany

Unit of Nutrition Environment and Cancer Cancer Epidemiology Research Programme Catalan Institute of Oncology Hospitalet de Llobregat Barcelona Spain

University of Pittsburgh Cancer Institute Pittsburgh PA USA

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J Thorac Dis. 2019 Jan;11(1):10-13. doi: 10.21037/jtd.2018.11.29. PubMed

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Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development