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 journalArticle

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 languageEnglish (US)
Pages (from-to)1483-1495
Number of pages13
JournalJournal of Thoracic Oncology
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Lung Neoplasms
Genes
Lymphotoxin-beta
Confidence Intervals
Exome
Morphogenesis
Alleles
BRCA2 Gene
Validation Studies
Genome-Wide Association Study
Zinc Fingers
DNA Repair
Chronic Obstructive Pulmonary Disease
Smoking
Genome
Lung
DNA

Keywords

  • Exome sequencing
  • Lung cancer
  • Rare variants
  • Susceptibility loci

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Liu, Y., Lusk, C. M., Cho, M. H., Silverman, E. K., Qiao, D., Zhang, R., ... 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

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

In: Journal of Thoracic Oncology, Vol. 13, No. 10, 01.10.2018, p. 1483-1495.

Research output: Contribution to journalArticle

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
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. / Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer. In: Journal of Thoracic Oncology. 2018 ; Vol. 13, No. 10. pp. 1483-1495.
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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 - 2018/10/1

Y1 - 2018/10/1

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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