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

Yanhong Liu; Christine M. Lusk; Michael H. Cho; Edwin K. Silverman; Dandi Qiao; Ruyang Zhang; Michael E. Scheurer; Farrah Kheradmand; David A. Wheeler; Spiridon Tsavachidis; Georgina Armstrong; Dakai Zhu; Ignacio I. Wistuba; Chi Wan B. Chow; Carmen Behrens; Claudio W. Pikielny; Christine Neslund-Dudas; Susan M. Pinney; Marshall Anderson; Elena Kupert; Joan Bailey-Wilson; Colette Gaba; Diptasri Mandal; Ming You; Mariza de Andrade; Ping Yang; John K. Field; Triantafillos Liloglou; Michael Davies; Jolanta Lissowska; Beata Swiatkowska; David Zaridze; Anush Mukeriya; Vladimir Janout; Ivana Holcatova; Dana Mates; Sasa Milosavljevic; Ghislaine Scelo; Paul Brennan; James McKay; Geoffrey Liu; Rayjean J. Hung; David C. Christiani; Ann G. Schwartz; Christopher I. Amos; Margaret R. Spitz

doi:10.1016/j.jtho.2018.06.016

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

Yanhong Liu, Christine M. Lusk, Michael H. Cho, Edwin K. Silverman, Dandi Qiao, Ruyang Zhang, Michael E. Scheurer, Farrah Kheradmand, David A. Wheeler, Spiridon Tsavachidis, Georgina Armstrong, Dakai Zhu, Ignacio I. Wistuba, Chi Wan B. Chow, Carmen Behrens, Claudio W. Pikielny, Christine Neslund-Dudas, Susan M. Pinney, Marshall Anderson, Elena KupertJoan Bailey-Wilson, Colette Gaba, Diptasri Mandal, Ming You, Mariza de Andrade, Ping Yang, John K. Field, Triantafillos Liloglou, Michael Davies, Jolanta Lissowska, Beata Swiatkowska, David Zaridze, Anush Mukeriya, Vladimir Janout, Ivana Holcatova, Dana Mates, Sasa Milosavljevic, Ghislaine Scelo, Paul Brennan, James McKay, Geoffrey Liu, Rayjean J. Hung, David C. Christiani, Ann G. Schwartz, Christopher I. Amos, Margaret R. Spitz

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1483-1495
Number of pages	13
Journal	Journal of Thoracic Oncology
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.jtho.2018.06.016
State	Published - Oct 2018

Keywords

Exome sequencing
Lung cancer
Rare variants
Susceptibility loci

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

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10.1016/j.jtho.2018.06.016

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Liu, Y., Lusk, C. M., Cho, M. H., Silverman, E. K., Qiao, D., Zhang, R., Scheurer, M. E., Kheradmand, F., Wheeler, D. A., Tsavachidis, S., Armstrong, G., Zhu, D., Wistuba, I. I., Chow, C. W. B., Behrens, C., Pikielny, C. W., Neslund-Dudas, C., Pinney, S. M., Anderson, M., ... Spitz, M. R. (2018). Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer. Journal of Thoracic Oncology, 13(10), 1483-1495. https://doi.org/10.1016/j.jtho.2018.06.016

Liu, Y, Lusk, CM, Cho, MH, Silverman, EK, Qiao, D, Zhang, R, Scheurer, ME, Kheradmand, F, Wheeler, DA, Tsavachidis, S, Armstrong, G, Zhu, D, Wistuba, II, Chow, CWB, Behrens, C, Pikielny, CW, Neslund-Dudas, C, Pinney, SM, Anderson, M, Kupert, E, Bailey-Wilson, J, Gaba, C, Mandal, D, You, M, de Andrade, M, Yang, P, Field, JK, Liloglou, T, Davies, M, Lissowska, J, Swiatkowska, B, Zaridze, D, Mukeriya, A, Janout, V, Holcatova, I, Mates, D, Milosavljevic, S, Scelo, G, Brennan, P, McKay, J, Liu, G, Hung, RJ, Christiani, DC, Schwartz, AG, Amos, CI & Spitz, MR 2018, 'Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer', Journal of Thoracic Oncology, vol. 13, no. 10, pp. 1483-1495. https://doi.org/10.1016/j.jtho.2018.06.016

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title = "Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer",

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.",

keywords = "Exome sequencing, Lung cancer, Rare variants, Susceptibility loci",

author = "Yanhong Liu and Lusk, {Christine M.} and Cho, {Michael H.} and Silverman, {Edwin K.} and Dandi Qiao and Ruyang Zhang and Scheurer, {Michael E.} and Farrah Kheradmand and Wheeler, {David A.} and Spiridon Tsavachidis and Georgina Armstrong and Dakai Zhu and Wistuba, {Ignacio I.} and Chow, {Chi Wan B.} and Carmen Behrens and Pikielny, {Claudio W.} and Christine Neslund-Dudas and Pinney, {Susan M.} and Marshall Anderson and Elena Kupert and Joan Bailey-Wilson and Colette Gaba and Diptasri Mandal and Ming You and {de Andrade}, Mariza and Ping Yang and Field, {John K.} and Triantafillos Liloglou and Michael Davies and Jolanta Lissowska and Beata Swiatkowska and David Zaridze and Anush Mukeriya and Vladimir Janout and Ivana Holcatova and Dana Mates and Sasa Milosavljevic and Ghislaine Scelo and Paul Brennan and James McKay and Geoffrey Liu and Hung, {Rayjean J.} and Christiani, {David C.} and Schwartz, {Ann G.} and Amos, {Christopher I.} and Spitz, {Margaret R.}",

note = "Publisher Copyright: {\textcopyright} 2018 International Association for the Study of Lung Cancer",

year = "2018",

month = oct,

doi = "10.1016/j.jtho.2018.06.016",

language = "English (US)",

volume = "13",

pages = "1483--1495",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "10",

}

TY - JOUR

T1 - Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

AU - Liu, Yanhong

AU - Lusk, Christine M.

AU - Cho, Michael H.

AU - Silverman, Edwin K.

AU - Qiao, Dandi

AU - Zhang, Ruyang

AU - Scheurer, Michael E.

AU - Kheradmand, Farrah

AU - Wheeler, David A.

AU - Tsavachidis, Spiridon

AU - Armstrong, Georgina

AU - Zhu, Dakai

AU - Wistuba, Ignacio I.

AU - Chow, Chi Wan B.

AU - Behrens, Carmen

AU - Pikielny, Claudio W.

AU - Neslund-Dudas, Christine

AU - Pinney, Susan M.

AU - Anderson, Marshall

AU - Kupert, Elena

AU - Bailey-Wilson, Joan

AU - Gaba, Colette

AU - Mandal, Diptasri

AU - You, Ming

AU - de Andrade, Mariza

AU - Yang, Ping

AU - Field, John K.

AU - Liloglou, Triantafillos

AU - Davies, Michael

AU - Lissowska, Jolanta

AU - Swiatkowska, Beata

AU - Zaridze, David

AU - Mukeriya, Anush

AU - Janout, Vladimir

AU - Holcatova, Ivana

AU - Mates, Dana

AU - Milosavljevic, Sasa

AU - Scelo, Ghislaine

AU - Brennan, Paul

AU - McKay, James

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Christiani, David C.

AU - Schwartz, Ann G.

AU - Amos, Christopher I.

AU - Spitz, Margaret R.

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

KW - Exome sequencing

KW - Lung cancer

KW - Rare variants

KW - Susceptibility loci

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

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