title: Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.
abstract: BACKGROUND
  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 severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC 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 10q25.1 was 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 β-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.
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Caleb F
authors.initials: CF
authors.lastname: Davis
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wheeler
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Spiridon
authors.initials: S
authors.lastname: Tsavachidis
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Armstrong
authors.affiliation: National Institutes of Health, Baltimore, MD, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Simpson
authors.affiliation: Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Diptasri
authors.initials: D
authors.lastname: Mandal
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kupert
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Donghai
authors.initials: D
authors.lastname: Xiong
authors.affiliation: Dartmouth College, Lebanon, NH, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pikielny
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Bailey-Wilson
authors.affiliation: The University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Colette
authors.initials: C
authors.lastname: Gaba
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: De Andrade
authors.affiliation: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Pinney
authors.affiliation: Dartmouth College, Lebanon, NH, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Baylor College of Medicine, Houston, TX, USA. Electronic address: spitz@bcm.edu.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D029424:Pulmonary Disease, Chronic Obstructive; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D012907:Smoking
chemical_list: D014408:Biomarkers, Tumor
keywords: Chronic obstructive pulmonary disease; Exome sequencing; Familial; Lung cancer; Single-nucleotide variants; Sporadic