Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10146/618240
Title:
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.
Authors:
Liu, Yanhong; Lusk, Christine M; Cho, Michael H; Silverman, Edwin K; Qiao, Dandi; Zhang, Ruyang; Scheurer, Michael E; Kheradmand, Farrah; Wheeler, David A; Tsavachidis, Spiridon; Armstrong, Georgina; Zhu, Dakai; Wistuba, Ignacio I; Chow, Chi-Wan B; Behrens, Carmen; Pikielny, Claudio W; Neslund-Dudas, Christine; Pinney, Susan M; Anderson, Marshall; Kupert, Elena; Bailey-Wilson, Joan; Gaba, Colette; Mandal, Diptasri; You, Ming; de Andrade, Mariza; Yang, Ping; Field, John K; Liloglou, Triantafillos; Davies, Michael; Lissowska, Jolanta; Swiatkowska, Beata; Zaridze, David; Mukeriya, Anush; Janout, Vladimir; Holcatova, Ivana; Mates, Dana; Milosavljevic, Sasa; Scelo, Ghislaine; Brennan, Paul; McKay, James; Liu, Geoffrey; Hung, Rayjean J; Christiani, David C; Schwartz, Ann G; Amos, Christopher I; Spitz, Margaret R
Abstract:
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.; 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.; 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.; Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
Affiliation:
Nofer Institute of Occupational Medicine
Citation:
J Thorac Oncol 2018, 13 (10):1483-1495
Journal:
Journal of Thoracic Oncology : official publication of the International Association for the Study of Lung Cancer
Issue Date:
Oct-2018
URI:
http://hdl.handle.net/10146/618240
DOI:
10.1016/j.jtho.2018.06.016
PubMed ID:
29981437
Additional Links:
https://www.sciencedirect.com/science/article/abs/pii/S1556086418307676?via%3Dihub
Type:
Article
Language:
en
ISSN:
1556-1380
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorLiu, Yanhongen
dc.contributor.authorLusk, Christine Men
dc.contributor.authorCho, Michael Hen
dc.contributor.authorSilverman, Edwin Ken
dc.contributor.authorQiao, Dandien
dc.contributor.authorZhang, Ruyangen
dc.contributor.authorScheurer, Michael Een
dc.contributor.authorKheradmand, Farrahen
dc.contributor.authorWheeler, David Aen
dc.contributor.authorTsavachidis, Spiridonen
dc.contributor.authorArmstrong, Georginaen
dc.contributor.authorZhu, Dakaien
dc.contributor.authorWistuba, Ignacio Ien
dc.contributor.authorChow, Chi-Wan Ben
dc.contributor.authorBehrens, Carmenen
dc.contributor.authorPikielny, Claudio Wen
dc.contributor.authorNeslund-Dudas, Christineen
dc.contributor.authorPinney, Susan Men
dc.contributor.authorAnderson, Marshallen
dc.contributor.authorKupert, Elenaen
dc.contributor.authorBailey-Wilson, Joanen
dc.contributor.authorGaba, Coletteen
dc.contributor.authorMandal, Diptasrien
dc.contributor.authorYou, Mingen
dc.contributor.authorde Andrade, Marizaen
dc.contributor.authorYang, Pingen
dc.contributor.authorField, John Ken
dc.contributor.authorLiloglou, Triantafillosen
dc.contributor.authorDavies, Michaelen
dc.contributor.authorLissowska, Jolantaen
dc.contributor.authorSwiatkowska, Beataen
dc.contributor.authorZaridze, Daviden
dc.contributor.authorMukeriya, Anushen
dc.contributor.authorJanout, Vladimiren
dc.contributor.authorHolcatova, Ivanaen
dc.contributor.authorMates, Danaen
dc.contributor.authorMilosavljevic, Sasaen
dc.contributor.authorScelo, Ghislaineen
dc.contributor.authorBrennan, Paulen
dc.contributor.authorMcKay, Jamesen
dc.contributor.authorLiu, Geoffreyen
dc.contributor.authorHung, Rayjean Jen
dc.contributor.authorChristiani, David Cen
dc.contributor.authorSchwartz, Ann Gen
dc.contributor.authorAmos, Christopher Ien
dc.contributor.authorSpitz, Margaret Ren
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.en
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.en
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.en
dc.description.abstractOur results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.en
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

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