-
Something wrong with this record ?
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer
Y. Liu, CM. Lusk, MH. Cho, EK. Silverman, D. Qiao, R. Zhang, ME. Scheurer, F. Kheradmand, DA. Wheeler, S. Tsavachidis, G. Armstrong, D. Zhu, II. Wistuba, CB. Chow, C. Behrens, CW. Pikielny, C. Neslund-Dudas, SM. Pinney, M. Anderson, E. Kupert, J....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
Grant support
R01 CA092824
NCI NIH HHS - United States
R01 HL110883
NHLBI NIH HHS - United States
U19 CA203654
NCI NIH HHS - United States
U19 CA148127
NCI NIH HHS - United States
HHSN268201200007C
NHLBI NIH HHS - United States
HHSN261201300011I
NCI NIH HHS - United States
P30 CA125123
NCI NIH HHS - United States
K01 HL129039
NHLBI NIH HHS - United States
R01 CA134433
NCI NIH HHS - United States
R01 CA141769
NCI NIH HHS - United States
R01 CA080127
NCI NIH HHS - United States
U01 CA076293
NCI NIH HHS - United States
P30 CA023108
NCI NIH HHS - United States
R01 CA060691
NCI NIH HHS - United States
HHSN261201300011C
CCR NIH HHS - United States
R01 CA134682
NCI NIH HHS - United States
T42 OH008416
NIOSH CDC HHS - United States
R01 CA127219
NCI NIH HHS - United States
R01 HL113264
NHLBI NIH HHS - United States
R01 CA074386
NCI NIH HHS - United States
K07 CA181480
NCI NIH HHS - United States
R01 HL089897
NHLBI NIH HHS - United States
R03 CA077118
NCI NIH HHS - United States
R01 HL089856
NHLBI NIH HHS - United States
R01 HL082487
NHLBI NIH HHS - United States
P50 CA090578
NCI NIH HHS - United States
P20 GM103534
NIGMS NIH HHS - United States
R35 CA197449
NCI NIH HHS - United States
R01 CA084354
NCI NIH HHS - United States
P30 CA022453
NCI NIH HHS - United States
R01 CA087895
NCI NIH HHS - United States
N01HG65404
NHGRI NIH HHS - United States
P30 ES006096
NIEHS NIH HHS - United States
- MeSH
- Genome-Wide Association Study methods MeSH
- Adult MeSH
- Genetic Variation genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Lung Neoplasms genetics pathology MeSH
- Risk Factors MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
Department of Pediatrics Baylor College of Medicine Houston Texas
Department of Public Health Sciences Henry Ford health System Detroit Michigan
Faculty of Health Sciences Palacky University Olomouc Czech Republic
Harvard University School of Public Health Boston Massachusetts
Institute for Clinical and Translational Research Baylor College of Medicine Houston Texas
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
Michael E DeBakey Veterans Affairs Medical Center
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
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
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc19035139
- 003
- CZ-PrNML
- 005
- 20191015105944.0
- 007
- ta
- 008
- 191007s2018 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.jtho.2018.06.016 $2 doi
- 035 __
- $a (PubMed)29981437
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Liu, Yanhong $u Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: yl10@bcm.edu.
- 245 10
- $a Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer / $c Y. Liu, CM. Lusk, MH. Cho, EK. Silverman, D. Qiao, R. Zhang, ME. Scheurer, F. Kheradmand, DA. Wheeler, S. Tsavachidis, G. Armstrong, D. Zhu, II. Wistuba, CB. Chow, C. Behrens, CW. Pikielny, C. Neslund-Dudas, SM. Pinney, M. Anderson, E. Kupert, J. Bailey-Wilson, C. Gaba, D. Mandal, M. You, M. de Andrade, P. Yang, JK. Field, T. Liloglou, M. Davies, J. Lissowska, B. Swiatkowska, D. Zaridze, A. Mukeriya, V. Janout, I. Holcatova, D. Mates, S. Milosavljevic, G. Scelo, P. Brennan, J. McKay, G. Liu, RJ. Hung, DC. Christiani, AG. Schwartz, CI. Amos, MR. Spitz,
- 520 9_
- $a 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.
- 650 _2
- $a dospělí $7 D000328
- 650 _2
- $a senioři $7 D000368
- 650 _2
- $a senioři nad 80 let $7 D000369
- 650 _2
- $a ženské pohlaví $7 D005260
- 650 _2
- $a genetická variace $x genetika $7 D014644
- 650 _2
- $a celogenomová asociační studie $x metody $7 D055106
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a nádory plic $x genetika $x patologie $7 D008175
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a lidé středního věku $7 D008875
- 650 _2
- $a rizikové faktory $7 D012307
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a Research Support, N.I.H., Extramural $7 D052061
- 655 _2
- $a Research Support, N.I.H., Intramural $7 D052060
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Lusk, Christine M $u Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
- 700 1_
- $a Cho, Michael H $u Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
- 700 1_
- $a Silverman, Edwin K $u Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
- 700 1_
- $a Qiao, Dandi $u Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
- 700 1_
- $a Zhang, Ruyang $u Harvard University School of Public Health, Boston, Massachusetts.
- 700 1_
- $a Scheurer, Michael E $u Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
- 700 1_
- $a Kheradmand, Farrah $u Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center; Houston, Texas.
- 700 1_
- $a Wheeler, David A $u Department of Molecular and Human Genetics, Human Genome Sequence Center, Baylor College of Medicine, Houston, Texas.
- 700 1_
- $a Tsavachidis, Spiridon $u Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas.
- 700 1_
- $a Armstrong, Georgina $u Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas.
- 700 1_
- $a Zhu, Dakai $u 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.
- 700 1_
- $a Wistuba, Ignacio I $u Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
- 700 1_
- $a Chow, Chi-Wan B $u Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
- 700 1_
- $a Behrens, Carmen $u Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
- 700 1_
- $a Pikielny, Claudio W $u Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire.
- 700 1_
- $a Neslund-Dudas, Christine $u Department of Public Health Sciences, Henry Ford health System, Detroit, Michigan.
- 700 1_
- $a Pinney, Susan M $u University of Cincinnati College of Medicine, Cincinnati, Ohio.
- 700 1_
- $a Anderson, Marshall $u University of Cincinnati College of Medicine, Cincinnati, Ohio.
- 700 1_
- $a Kupert, Elena $u University of Cincinnati College of Medicine, Cincinnati, Ohio.
- 700 1_
- $a Bailey-Wilson, Joan $u National Human Genome Research Institute, Bethesda, Maryland.
- 700 1_
- $a Gaba, Colette $u The University of Toledo College of Medicine, Toledo, Ohio.
- 700 1_
- $a Mandal, Diptasri $u Louisiana State University Health Sciences Center, New Orleans, Louisiana.
- 700 1_
- $a You, Ming $u Medical College of Wisconsin, Milwaukee, Wisconsin.
- 700 1_
- $a de Andrade, Mariza $u Mayo Clinic College of Medicine, Rochester, Minnesota.
- 700 1_
- $a Yang, Ping $u Mayo Clinic College of Medicine, Rochester, Minnesota.
- 700 1_
- $a Field, John K $u Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, United Kingdom.
- 700 1_
- $a Liloglou, Triantafillos $u Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, United Kingdom.
- 700 1_
- $a Davies, Michael $u Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, United Kingdom.
- 700 1_
- $a Lissowska, Jolanta $u Maria Sklodowska-Curie Institute of Oncology Center, Warsaw, Poland.
- 700 1_
- $a Swiatkowska, Beata $u Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland.
- 700 1_
- $a Zaridze, David $u Russian N. N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
- 700 1_
- $a Mukeriya, Anush $u Russian N. N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
- 700 1_
- $a Janout, Vladimir $u Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic.
- 700 1_
- $a Holcatova, Ivana $u Institute of Public Health and Preventive Medicine, Charles University, Second Faculty of Medicine, Prague, Czech Republic.
- 700 1_
- $a Mates, Dana $u National Institute of Public Health, Bucharest, Romania.
- 700 1_
- $a Milosavljevic, Sasa $u International Organization for Cancer Prevention and Research, Belgrade, Serbia.
- 700 1_
- $a Scelo, Ghislaine $u International Agency for Research on Cancer, Lyon, France.
- 700 1_
- $a Brennan, Paul $u International Agency for Research on Cancer, Lyon, France.
- 700 1_
- $a McKay, James $u International Agency for Research on Cancer, Lyon, France.
- 700 1_
- $a Liu, Geoffrey $u Princess Margaret Cancer Center, Toronto, Ontario, Canada.
- 700 1_
- $a Hung, Rayjean J $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
- 700 1_
- $a Christiani, David C $u Harvard University School of Public Health, Boston, Massachusetts.
- 700 1_
- $a Schwartz, Ann G $u Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
- 700 1_
- $a Amos, Christopher I $u 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.
- 700 1_
- $a Spitz, Margaret R $u Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, Texas.
- 773 0_
- $w MED00186087 $t Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer $x 1556-1380 $g Roč. 13, č. 10 (2018), s. 1483-1495
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/29981437 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20191007 $b ABA008
- 991 __
- $a 20191015110410 $b ABA008
- 999 __
- $a ok $b bmc $g 1451799 $s 1073689
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2018 $b 13 $c 10 $d 1483-1495 $e 20180704 $i 1556-1380 $m Journal of thoracic oncology $n J Thorac Oncol $x MED00186087
- GRA __
- $a R01 CA092824 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 HL110883 $p NHLBI NIH HHS $2 United States
- GRA __
- $a U19 CA203654 $p NCI NIH HHS $2 United States
- GRA __
- $a U19 CA148127 $p NCI NIH HHS $2 United States
- GRA __
- $a HHSN268201200007C $p NHLBI NIH HHS $2 United States
- GRA __
- $a HHSN261201300011I $p NCI NIH HHS $2 United States
- GRA __
- $a P30 CA125123 $p NCI NIH HHS $2 United States
- GRA __
- $a K01 HL129039 $p NHLBI NIH HHS $2 United States
- GRA __
- $a R01 CA134433 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 CA141769 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 CA080127 $p NCI NIH HHS $2 United States
- GRA __
- $a U01 CA076293 $p NCI NIH HHS $2 United States
- GRA __
- $a P30 CA023108 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 CA060691 $p NCI NIH HHS $2 United States
- GRA __
- $a HHSN261201300011C $p CCR NIH HHS $2 United States
- GRA __
- $a R01 CA134682 $p NCI NIH HHS $2 United States
- GRA __
- $a T42 OH008416 $p NIOSH CDC HHS $2 United States
- GRA __
- $a R01 CA127219 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 HL113264 $p NHLBI NIH HHS $2 United States
- GRA __
- $a R01 CA074386 $p NCI NIH HHS $2 United States
- GRA __
- $a K07 CA181480 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 HL089897 $p NHLBI NIH HHS $2 United States
- GRA __
- $a R03 CA077118 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 HL089856 $p NHLBI NIH HHS $2 United States
- GRA __
- $a R01 HL082487 $p NHLBI NIH HHS $2 United States
- GRA __
- $a P50 CA090578 $p NCI NIH HHS $2 United States
- GRA __
- $a P20 GM103534 $p NIGMS NIH HHS $2 United States
- GRA __
- $a R35 CA197449 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 CA084354 $p NCI NIH HHS $2 United States
- GRA __
- $a P30 CA022453 $p NCI NIH HHS $2 United States
- GRA __
- $a R01 CA087895 $p NCI NIH HHS $2 United States
- GRA __
- $a N01HG65404 $p NHGRI NIH HHS $2 United States
- GRA __
- $a P30 ES006096 $p NIEHS NIH HHS $2 United States
- LZP __
- $a Pubmed-20191007