BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

Dan L Duncan Comprehensive Cancer Center Department of Medicine Baylor College of Medicine Houston Texas

Dan L Duncan Comprehensive Cancer Center Department of Medicine Baylor College of Medicine Houston Texas; Institute for Clinical and Translational Research Baylor College of Medicine Houston Texas

Dan L Duncan Comprehensive Cancer Center Department of Medicine Baylor College of Medicine Houston Texas; Michael E DeBakey Veterans Affairs Medical Center; Houston Texas

Department of Biomedical Data Science Geisel School of Medicine Dartmouth College Lebanon New Hampshire

Department of Molecular and Human Genetics Human Genome Sequence Center Baylor College of Medicine Houston Texas

Department of Pediatrics Baylor College of Medicine Houston Texas

Department of Public Health Sciences Henry Ford health System Detroit Michigan

Department of Thoracic Head and Neck Medical Oncology The University of Texas M D Anderson Cancer Center Houston Texas

Department of Translational Molecular Pathology The University of Texas M D Anderson Cancer Center Houston Texas

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Harvard University School of Public Health Boston Massachusetts

Institute of Public Health and Preventive Medicine Charles University 2nd Faculty of Medicine Prague Czech Republic

International Agency for Research on Cancer Lyon France

International Organization for Cancer Prevention and Research Belgrade Serbia

Karmanos Cancer Institute Wayne State University Detroit Michigan

Louisiana State University Health Sciences Center New Orleans Louisiana

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Maria Sklodowska Curie Institute of Oncology Center Warsaw Poland

Mayo Clinic College of Medicine Rochester Minnesota

Medical College of Wisconsin Milwaukee Wisconsin

National Human Genome Research Institute Bethesda Maryland

National Institute of Public Health Bucharest Romania

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Princess Margaret Cancer Center Toronto Ontario Canada

Roy Castle Lung Cancer Research Programme The University of Liverpool Department of Molecular and Clinical Cancer Medicine Liverpool United Kingdom

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

The University of Toledo College of Medicine Toledo Ohio

University of Cincinnati College of Medicine Cincinnati Ohio

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Rare deleterious germline variants and risk of lung cancer