Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

American Cancer Society Inc Atlanta GA USA

Biomedical Data Science Geisel School of Medicine at Dartmouth Hanover NH USA

British Columbia Cancer Agency Vancouver Canada

Cancer Registry and Histopathology Department Civic M P Arezzo Hospital Asp Ragusa Italy

Charles University 1st Faculty of Medicine Prague Czech Republic

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

Clinical Center of Serbia Clinic for Pulmonology School of Medicine University of Belgrade Belgrade Serbia

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen Denmark

Dan L Duncan Comprehensive Cancer Center 7200 Cambridge St 7th Floor Houston TX 77030 USA

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

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

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 University of Milan Milan Italy

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York USA

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 Russian Federation

Department of Epidemiology Geisel School of Medicine Hanover NH USA

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

Department of Integrative Bioscience and Biotechnology Sejong University Gwangjin gu Seoul Republic of Korea

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Medicine Massachusetts General Hospital Harvard Boston MA USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Oncology and Metabolism University of Sheffield Sheffield UK

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

Department of Pathology Lund University Lund Sweden

Department of Pathology Memorial Sloan Kettering Cancer Center New York USA

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 Preventive Medicine Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles CA USA

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 Göttingen Germany

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

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Faculty of Medicine Lund University Lund Sweden

Fred Hutchinson Cancer Research Center Seattle WA USA

Genetic Epidemiology Group Department of Health Sciences University of Leicester Leicester LE1 7RH UK

Hellenic Health Foundation Athens GR Greece

Institut universitaire de cardiologie et de pneumologie de Québec Department of Molecular Medicine Laval University Québec Canada

Institute of Pneumology Marius Nasta Bucharest Romania

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

Lunenfeld Tanenbaum Research Institute Sinai Health System and University of Toronto Toronto Canada

Marie Josée and Henry R KravisCenter for Molecular Oncology Memorial Sloan Kettering Cancer Center New York USA

Merck Research Laboratories Genetics and Pharmacogenomics Boston MA USA

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 Canada

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

Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands

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

Roy Castle lung Cancer Research Programme Institute of Translational Medicine University of Liverpool Liverpool United Kingdom

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

Swedish Medical Group Seattle WA USA

The Institute for Clinical and Translational Research Baylor College of Medicine Houston TX USA

The Institute of Cancer Research London UK

The Norris Cotton Cancer Center Dartmouth Hitchcock Medical Center Lebanon NH USA

The University of British Columbia Centre for Heart Lung Innovation St Paul's Hospital Vancouver BC Canada

Thoraxklinik at University Hospital Heidelberg Heidelberg Germany

Translational Lung Research Center Heidelberg Heidelberg Germany

University Health Network The Princess Margaret Cancer Centre Toronto CA USA

University of Groningen University Medical Center Groningen Department of Pathology and Medical Biology GRIAC research institute Groningen The Netherlands

University of Kentucky Markey Cancer Center Lexington KY USA

University of Pittsburgh Cancer Institute Pittsburgh USA

University of Salzburg and Cancer Cluster Salzburg Salzburg Austria

University of Toronto Toronto Canada

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Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia

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