We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

] Center for Genomic Medicine Department of Community and Family Medicine Geisel School of Medicine Dartmouth College Lebanon New Hampshire USA [2] [3]

] Department of Community Medicine Faculty of Health Sciences University of Tromsø Tromsø Norway [2] Department of Research Cancer Registry of Norway Oslo Norway [3] Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden [4] Samfundet Folkhälsan Helsinki Finland

] Department of Epidemiology and Biostatistics School of Public Health Imperial College London UK [2] National Institute for Public Health and the Environment Bilthoven The Netherlands [3] Department of Gastroenterology and Hepatology University Medical Centre Utrecht The Netherlands

] Department of Epidemiology and Biostatistics School of Public Health Imperial College London UK [2] Unit of Molecular and Genetic Epidemiology HuGeF Foundation Torino Italy

] Department of Epidemiology Harvard School of Public Health Boston Massachusetts USA [2] Bureau of Epidemiologic Research Academy of Athens Athens Greece [3] Hellenic Health Foundation Athens Greece

] Department of Health and Human Services Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda Maryland USA [2] [3]

] Department of Oncology Cambridge University Hospitals National Health Service Foundation Trust Cambridge UK [2] Addenbrooke's Hospital Cambridge Biomedical Campus Cambridge UK

] Division of Cancer Epidemiology DKFZ Heidelberg Germany [2] Translational Lung Research Center Heidelberg Heidelberg Germany

] Division of Epigenomics and Cancer Risk Factors German Cancer Research Center Heidelberg Germany

] Division of Genetics and Epidemiology Institute of Cancer Research Sutton Surrey UK [2]

] Division of Genetics and Epidemiology Institute of Cancer Research Sutton Surrey UK [2] [3]

] Estonian Genome Center Institute of Molecular and Cell Biology Tartu Estonia [2] Department of Genetic Medicine and Development University of Geneva Medical School Geneva Switzerland

] INSERM Centre for Research in Epidemiology and Population Health U1018 Nutrition Hormones and Women's Health Team Villejuif France [2] Université Paris Sud UMRS 1018 Villejuif France [3] Institut Gustave Roussy Villejuif France

] International Agency for Research on Cancer Lyon France [2] [3]

] Translational Lung Research Center Heidelberg Heidelberg Germany [2] Department of Thoracic Surgery Thoraxklinik at University Hospital Heidelberg Heidelberg Germany

1st Faculty of Medicine Institute of Hygiene and Epidemiology Charles University Prague Prague Czech Republic

Cancer Research UK Cambridge Institute Li Ka Shing Centre Cambridge UK

Center for Genomic Medicine Department of Community and Family Medicine Geisel School of Medicine Dartmouth College Lebanon New Hampshire USA

Centre d'Etude du Polymorphisme Humain Paris France

Dan L Duncan Cancer Center Baylor College of Medicine Houston Texas USA

Danish Cancer Society Research Center Copenhagen Denmark

Department of Biomedicine University of Bergen Bergen Norway

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Community Medicine University of Tromsø Tromsø Norway

Department of Environmental Health Harvard School of Public Health Boston Massachusetts USA

Department of Epidemiology and Biostatistics School of Public Health Imperial College London UK

Department of Epidemiology Institute of Occupational Medicine Lodz Poland

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

Department of Genetic Epidemiology University of Göttingen Göttingen Germany

Department of Genetics and Pathology International Hereditary Cancer Center Pomeranian Medical University Szczecin Poland

Department of Genetics University of Texas MD Anderson Cancer Center Houston Texas USA

Department of Health and Human Services Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda Maryland USA

Department of Laboratory Medicine Children's and Women's Health Faculty of Medicine Norwegian University of Science and Technology Trondheim Norway

Department of Laboratory Medicine Children's and Women's Health Norwegian University of Science and Technology Trondheim Norway

Department of Public Health and General Practice Faculty of Medicine Norwegian University of Science and Technology Trondheim Norway

Department of Radiation Sciences Umeå Universitet Umeå Sverige Sweden

Division of Epigenomics and Cancer Risk Factors German Cancer Research Center Heidelberg Germany

Division of Genetics and Epidemiology Institute of Cancer Research Sutton Surrey UK

eCODE Genetics Amgen Reykjavik Iceland

Epidemiology Research Program American Cancer Society Atlanta Georgia USA

Estonian Genome Center Institute of Molecular and Cell Biology Tartu Estonia

Fred Hutchinson Cancer Research Center Seattle Washington USA

Information Management Services Inc Rockville Maryland USA

INSERM U946 Paris France

Institute of Carcinogenesis Russian N N Blokhin Cancer Research Centre Moscow Russia

Institute of Molecular and Cell Biology University of Tartu Tartu Estonia

International Agency for Research on Cancer Lyon France

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

National Institute of Environmental Health Budapest Hungary

National Institute of Public Health Bucharest Romania

Palacky University Olomouc Czech Republic

Princess Margaret Hospital University Health Network Toronto Ontario Canada

Regional Authority of Public Health Banská Bystrica Slovak Republic

The M Sklodowska Curie Memorial Cancer Center and Institute of Oncology Warsaw Poland

Unit of Nutrition Environment and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Barcelona Spain

University of Cambridge School of Clinical Medicine Clinical Gerontology Unit Addenbrooke's Hospital Cambridge UK

Erratum v

Nat Genet. 2017 Mar 30;49(4):651. doi: 10.1038/ng0417-651a. PubMed

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Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden

Rare deleterious germline variants and risk of lung cancer

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract