Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer

Yanhong Liu, Farrah Kheradmand, Caleb F. Davis, Michael E. Scheurer, David Wheeler, Spiridon Tsavachidis, Georgina Armstrong, Claire Simpson, Diptasri Mandal, Elena Kupert, Marshall Anderson, Ming You, Donghai Xiong, Claudio Pikielny, Ann G. Schwartz, Joan Bailey-Wilson, Colette Gaba, Mariza De Andrade, Ping Yang, Susan M. Pinney & 2 others Christopher I. Amos, Margaret R. Spitz

Research output: Contribution to journalArticle

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Abstract

Introduction: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants. Methods: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severeCOPD(inwhomsmoking is considered the overwhelming determinant)-and54unique familialLC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). Results: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine b-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). Conclusions: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalJournal of Thoracic Oncology
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2016

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Exome
Germ-Line Mutation
Lung Neoplasms
Mutation
Genome-Wide Association Study
Smoking
Cholinergic Receptors
Gene Frequency
Chronic Obstructive Pulmonary Disease
Iron Regulatory Protein 2
Genome
Databases
Rare Diseases
Genes
Phenotype
Lung

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Liu, Y., Kheradmand, F., Davis, C. F., Scheurer, M. E., Wheeler, D., Tsavachidis, S., ... Spitz, M. R. (2016). Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer. Journal of Thoracic Oncology, 11(1), 52-61. https://doi.org/10.1016/j.jtho.2015.09.015

Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer. / Liu, Yanhong; Kheradmand, Farrah; Davis, Caleb F.; Scheurer, Michael E.; Wheeler, David; Tsavachidis, Spiridon; Armstrong, Georgina; Simpson, Claire; Mandal, Diptasri; Kupert, Elena; Anderson, Marshall; You, Ming; Xiong, Donghai; Pikielny, Claudio; Schwartz, Ann G.; Bailey-Wilson, Joan; Gaba, Colette; De Andrade, Mariza; Yang, Ping; Pinney, Susan M.; Amos, Christopher I.; Spitz, Margaret R.

In: Journal of Thoracic Oncology, Vol. 11, No. 1, 01.01.2016, p. 52-61.

Research output: Contribution to journalArticle

Liu, Y, Kheradmand, F, Davis, CF, Scheurer, ME, Wheeler, D, Tsavachidis, S, Armstrong, G, Simpson, C, Mandal, D, Kupert, E, Anderson, M, You, M, Xiong, D, Pikielny, C, Schwartz, AG, Bailey-Wilson, J, Gaba, C, De Andrade, M, Yang, P, Pinney, SM, Amos, CI & Spitz, MR 2016, 'Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer', Journal of Thoracic Oncology, vol. 11, no. 1, pp. 52-61. https://doi.org/10.1016/j.jtho.2015.09.015
Liu, Yanhong ; Kheradmand, Farrah ; Davis, Caleb F. ; Scheurer, Michael E. ; Wheeler, David ; Tsavachidis, Spiridon ; Armstrong, Georgina ; Simpson, Claire ; Mandal, Diptasri ; Kupert, Elena ; Anderson, Marshall ; You, Ming ; Xiong, Donghai ; Pikielny, Claudio ; Schwartz, Ann G. ; Bailey-Wilson, Joan ; Gaba, Colette ; De Andrade, Mariza ; Yang, Ping ; Pinney, Susan M. ; Amos, Christopher I. ; Spitz, Margaret R. / Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer. In: Journal of Thoracic Oncology. 2016 ; Vol. 11, No. 1. pp. 52-61.
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abstract = "Introduction: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants. Methods: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severeCOPD(inwhomsmoking is considered the overwhelming determinant)-and54unique familialLC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). Results: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine b-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). Conclusions: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.",
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T1 - Focused analysis of exome sequencing data for rare germline mutations in familial and sporadic lung cancer

AU - Liu, Yanhong

AU - Kheradmand, Farrah

AU - Davis, Caleb F.

AU - Scheurer, Michael E.

AU - Wheeler, David

AU - Tsavachidis, Spiridon

AU - Armstrong, Georgina

AU - Simpson, Claire

AU - Mandal, Diptasri

AU - Kupert, Elena

AU - Anderson, Marshall

AU - You, Ming

AU - Xiong, Donghai

AU - Pikielny, Claudio

AU - Schwartz, Ann G.

AU - Bailey-Wilson, Joan

AU - Gaba, Colette

AU - De Andrade, Mariza

AU - Yang, Ping

AU - Pinney, Susan M.

AU - Amos, Christopher I.

AU - Spitz, Margaret R.

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N2 - Introduction: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants. Methods: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severeCOPD(inwhomsmoking is considered the overwhelming determinant)-and54unique familialLC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). Results: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine b-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). Conclusions: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.

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