Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.

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

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

Department of Biomedical Data Science Geisel School of Medicine Dartmouth College Lebanon NH USA

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Pediatrics Baylor College of Medicine Houston TX USA

Department of Thoracopulmonary Pathology Service of Pathology Clinical Center of Serbia Belgrade Serbia

Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer Center Houston TX USA

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Harvard University T H Chan School of Public Health Boston MA USA

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

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

International Agency for Research on Cancer Lyon France

Karmanos Cancer Institute Wayne State University Detroit MI USA

Louisiana State University Health Sciences Center New Orleans LA USA

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto ON Canada

M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Mayo Clinic College of Medicine Rochester MN USA

Mayo Clinic College of Medicine Scottsdale AZ USA

Medical College of Wisconsin Milwaukee WI USA

Michael E DeBakey Veterans Affairs Medical Center Houston TX USA

National Human Genome Research Institute Bethesda MD USA

National Institute of Public Health Bucharest Romania

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Princess Margaret Cancer Center Toronto ON Canada

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

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

The University of Toledo College of Medicine Toledo OH USA

University of Cincinnati College of Medicine Cincinnati OH USA

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