The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Baylor College of Medicine Houston TX USA

Biomedical Data Science Department Dartmouth College Hanover NH USA

British Columbia Cancer Agency Vancouver Canada

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

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

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen Denmark

Department of Biomedical Data Science Dartmouth College Hanover NH USA

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 Denmark

Department of Clinical Science University of Bergen Bergen Norway

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

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

Department of Epidemiology and Prevention N N Blokhin Russian Cancer Research Center Moscow Russian Federation

Department of Epidemiology Geisel School of Medicine Hanover NH USA

Department of Epidemiology Program in Molecular and Genetic Epidemiology Harvard School of Public Health Boston MA USA

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

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 Medical Biosciences Umeå University Umeå Sweden

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

Department of Oncology University of Sheffield Sheffield UK

Department of Pathology Lund University Lund Sweden

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

Department of Preventive Medicine IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Department of Radiation Sciences Umeå University Umeå Sweden

Department of Surgery National Tuberculosis and Lung Diseases Research Institute Warsaw Poland

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

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

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

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine Lund University Lund Sweden

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Fred Hutchinson Cancer Research Center Seattle WA USA

German Center for Lung Research Heidelberg Germany

Hellenic Health Foundation Athens Greece

Indiana University Bloomington IN USA

Institute of Pneumology Marius Nasta Bucharest Romania

Institute of Translational Medicine University of Liverpool Liverpool UK

International Agency for Research on Cancer World Health Organization Lyon France

International Organization for Cancer Prevention and Research Belgrade Serbia

IUOPA University of Oviedo and CIBERESP Faculty of Medicine Campus del Cristo s n Oviedo Spain

Laval University Quebec QC Canada

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital University of Toronto Toronto Canada

M Sklodowska Curie Cancer Center Institute of Oncology Warsaw Poland

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

National Institute for Health Research Leicester Respiratory Biomedical Research Unit Glenfield Hospital Leicester UK

National Institute of Occupational Health Oslo Norway

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Princess Margaret Cancer Centre Toronto ON Canada

Radboud University Medical Center Nijmegen The Netherlands

Research Unit of Molecular Epidemiology Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

School of Health and Related Research University of Sheffield Sheffield UK

School of Public Health St Mary's Campus Imperial College London London UK

Section for Epidemiology Department of Public Health Aarhus University Aarhus Denmark

Swedish Medical Group Seattle WA USA

The Institute of Cancer Research London UK

Thoraxklinik at University Hospital Heidelberg Translational Lung Research Center Heidelberg Heidelberg Germany

Translational Lung Research Center Heidelberg Heidelberg Germany

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona Spain

University Health Network The Princess Margaret Cancer Centre Toronto CA USA

University of Kentucky Markey Cancer Center Lexington KY USA

University of Pittsburgh Cancer Institute Pittsburgh PA USA

University of Salzburg and Cancer Cluster Salzburg Austria

University of Toronto Toronto ON Canada

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