title: Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.
abstract: BACKGROUND
  Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.
  
  
  METHODS
  1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.
  
  
  RESULTS
  The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)).
  
  
  CONCLUSIONS
  Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.
  
  
  CONCLUSIONS
  Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
authors.affiliation: Program in Cancer Genetics, Helen Diller Family Comprehensive Cancer Cente, San Francisco, CA, USA. kyle.walsh@ucsf.edu
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Gorlov
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Huifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Lu
authors.forename: Angela S
authors.initials: AS
authors.lastname: Wenzlaff
authors.forename: Jennette D
authors.initials: JD
authors.lastname: Sison
authors.forename: Chongjuan
authors.initials: C
authors.lastname: Wei
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Lloyd
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
mesh_terms: D000230:Adenocarcinoma / Q000208:ethnology / Q000209:etiology / Q000473:pathology; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000208:ethnology / Q000209:etiology / Q000473:pathology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000208:ethnology / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011506:Proteins / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D012307:Risk Factors; D055752:Small Cell Lung Carcinoma / Q000208:ethnology / Q000209:etiology / Q000473:pathology; D019098:Telomerase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; D011978:Receptors, Nicotinic; C092008:PRRC2A protein, human; C509186:TERT protein, human; D019098:Telomerase