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dc.contributor.authorLiu, Yanhong
dc.contributor.authorLusk, Christine M
dc.contributor.authorCho, Michael H
dc.contributor.authorSilverman, Edwin K
dc.contributor.authorQiao, Dandi
dc.contributor.authorZhang, Ruyang
dc.contributor.authorScheurer, Michael E
dc.contributor.authorKheradmand, Farrah
dc.contributor.authorWheeler, David A
dc.contributor.authorTsavachidis, Spiridon
dc.contributor.authorArmstrong, Georgina
dc.contributor.authorZhu, Dakai
dc.contributor.authorWistuba, Ignacio I
dc.contributor.authorChow, Chi-Wan B
dc.contributor.authorBehrens, Carmen
dc.contributor.authorPikielny, Claudio W
dc.contributor.authorNeslund-Dudas, Christine
dc.contributor.authorPinney, Susan M
dc.contributor.authorAnderson, Marshall
dc.contributor.authorKupert, Elena
dc.contributor.authorBailey-Wilson, Joan
dc.contributor.authorGaba, Colette
dc.contributor.authorMandal, Diptasri
dc.contributor.authorYou, Ming
dc.contributor.authorde Andrade, Mariza
dc.contributor.authorYang, Ping
dc.contributor.authorField, John K
dc.contributor.authorLiloglou, Triantafillos
dc.contributor.authorDavies, Michael
dc.contributor.authorLissowska, Jolanta
dc.contributor.authorSwiatkowska, Beata
dc.contributor.authorZaridze, David
dc.contributor.authorMukeriya, Anush
dc.contributor.authorJanout, Vladimir
dc.contributor.authorHolcatova, Ivana
dc.contributor.authorMates, Dana
dc.contributor.authorMilosavljevic, Sasa
dc.contributor.authorScelo, Ghislaine
dc.contributor.authorBrennan, Paul
dc.contributor.authorMcKay, James
dc.contributor.authorLiu, Geoffrey
dc.contributor.authorHung, Rayjean J
dc.contributor.authorChristiani, David C
dc.contributor.authorSchwartz, Ann G
dc.contributor.authorAmos, Christopher I
dc.contributor.authorSpitz, Margaret R
dc.date.accessioned2018-12-04T10:14:43Z
dc.date.available2018-12-04T10:14:43Z
dc.date.issued2018-10
dc.identifier.citationJ Thorac Oncol 2018, 13 (10):1483-1495en
dc.identifier.issn1556-1380
dc.identifier.pmid29981437
dc.identifier.doi10.1016/j.jtho.2018.06.016
dc.identifier.urihttp://hdl.handle.net/10146/618240
dc.description.abstractGenome-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.
dc.description.abstractGermline 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.
dc.description.abstractWe 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.
dc.description.abstractOur results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
dc.language.isoenen
dc.relation.urlhttps://www.sciencedirect.com/science/article/abs/pii/S1556086418307676?via%3Dihuben
dc.rightsArchived with thanks to Journal of thoracic oncology : official publication of the International Association for the Study of Lung Canceren
dc.subjectExome sequencingen
dc.subjectLung canceren
dc.subjectRare variantsen
dc.subjectSusceptibility locien
dc.titleRare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.en
dc.typeArticleen
dc.contributor.departmentNofer Institute of Occupational Medicineen
dc.identifier.journalJournal of Thoracic Oncology : official publication of the International Association for the Study of Lung Canceren
html.description.abstractGenome-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.
html.description.abstractGermline 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.
html.description.abstractWe 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.
html.description.abstractOur 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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