Yanhong Liu1, Christine M Lusk2, Michael H Cho3, Edwin K Silverman3, Dandi Qiao3, Ruyang Zhang4, Michael E Scheurer5, Farrah Kheradmand6, David A Wheeler7, Spiridon Tsavachidis8, Georgina Armstrong8, Dakai Zhu9, Ignacio I Wistuba10, Chi-Wan B Chow10, Carmen Behrens11, Claudio W Pikielny12, Christine Neslund-Dudas13, Susan M Pinney14, Marshall Anderson14, Elena Kupert14, Joan Bailey-Wilson15, Colette Gaba16, Diptasri Mandal17, Ming You18, Mariza de Andrade19, Ping Yang19, John K Field20, Triantafillos Liloglou20, Michael Davies20, Jolanta Lissowska21, Beata Swiatkowska22, David Zaridze23, Anush Mukeriya23, Vladimir Janout24, Ivana Holcatova25, Dana Mates26, Sasa Milosavljevic27, Ghislaine Scelo28, Paul Brennan28, James McKay28, Geoffrey Liu29, Rayjean J Hung30, David C Christiani4, Ann G Schwartz2, Christopher I Amos9, Margaret R Spitz8. 1. Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: yl10@bcm.edu. 2. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. 3. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 4. Harvard University School of Public Health, Boston, Massachusetts. 5. Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 6. Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center; Houston, Texas. 7. Department of Molecular and Human Genetics, Human Genome Sequence Center, Baylor College of Medicine, Houston, Texas. 8. Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas. 9. 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. 10. Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 11. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 12. Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire. 13. Department of Public Health Sciences, Henry Ford health System, Detroit, Michigan. 14. University of Cincinnati College of Medicine, Cincinnati, Ohio. 15. National Human Genome Research Institute, Bethesda, Maryland. 16. The University of Toledo College of Medicine, Toledo, Ohio. 17. Louisiana State University Health Sciences Center, New Orleans, Louisiana. 18. Medical College of Wisconsin, Milwaukee, Wisconsin. 19. Mayo Clinic College of Medicine, Rochester, Minnesota. 20. Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, United Kingdom. 21. Maria Sklodowska-Curie Institute of Oncology Center, Warsaw, Poland. 22. Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland. 23. Russian N. N. Blokhin Cancer Research Centre, Moscow, Russian Federation. 24. Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic. 25. Institute of Public Health and Preventive Medicine, Charles University, Second Faculty of Medicine, Prague, Czech Republic. 26. National Institute of Public Health, Bucharest, Romania. 27. International Organization for Cancer Prevention and Research, Belgrade, Serbia. 28. International Agency for Research on Cancer, Lyon, France. 29. Princess Margaret Cancer Center, Toronto, Ontario, Canada. 30. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Abstract
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.
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.
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